Biaryl compositions and methods for modulating a kinase cascade

ABSTRACT

The application relates to biaryl compounds, pharmaceutical compositions comprising the compounds, and methods of use the compounds for treating cell proliferation disorders.

RELATED APPLICATION

This application claims priority to, and the benefit of, U.S.Provisional Application No. 62/374,201, filed on Aug. 12, 2016, thecontents of which are incorporated herein by reference in theirentirety.

BACKGROUND

Signal transduction is any process by which a cell converts one kind ofsignal or stimulus into another. One class of molecules involved insignal transduction is the kinase family of enzymes.

Protein kinases are a large class of enzymes which catalyze the transferof the □-phosphate from ATP to the hydroxyl group on the side chain ofSer/Thr or Tyr in proteins and peptides and are intimately involved inthe control of various important cell functions, perhaps most notably:signal transduction, differentiation, and proliferation.

Phosphorylation of proteins by kinases is an important mechanism insignal transduction for regulation of enzyme activity. The tyrosinekinases are divided into two groups; those that are cytoplasmic proteinsand the transmembrane receptor-linked kinases.

Because kinases are involved in the regulation of a wide variety ofnormal cellular signal transduction pathways (e.g., cell growth,differentiation, survival, adhesion, migration, etc.), kinases arethought to play a role in a variety of diseases and disorders. Thus,modulation of kinase signaling cascades may be an important way to treator prevent such diseases and disorders. One promising potentialtherapeutic use for protein kinase or protein phosphatase inhibitors isas anti-cancer agents.

Small molecule interference with tubulin dynamics has broad and profoundeffect on a cell. When small molecules bind to tubulin they caninterfere with the dynamics of microtubules formed from tubulin, eitherby stabilizing the formed microtubules so they cannot break down or bypreventing new formation of microtubules by polymerization.

The effect of small molecules interfering with tubulin dynamics canmanifest in the suppression of the cell's ability to proliferate.Interference by small molecules on tubulin dynamics can force the cellto arrest at the G2/M point in the cell cycle, ceasing mitosis, andtriggering apoptosis. This action makes these small moleculesefficacious in treating human diseases associated with uncontrolled cellproliferation. Efficacy in treating hyper-proliferative disorders hasbeen proven by compounds such as Paclitaxel (a microtubule stabilizer)and Vinblastin (a tubulin polymerization inhibitor) in human subjects.

Tubulin-targeting small molecules can also affect vascularization oftissue. Several tubulin polymerization inhibitors have been demonstratedto affect the abnormal vascularization of tumors. These effects manifestin, e.g., normalization of the vascular network and cutting off bloodflow to cancerous tumors, resulting in necrosis. These vascular effectsmay also be useful for other disease states resulting from abnormalvascularization, such as ocular myopathy.

There is a need for small molecule compounds that modulate the kinasesignaling cascade as well as tubulin dynamics. The present applicationaddresses such need.

SUMMARY

Compounds of the application are useful in modulating a component of thekinase signaling cascade or in targeting tubulin. Some compounds may beuseful in modulation of more than one component of a kinase signalingcascade. The compounds of the present application are useful aspharmaceutical agents. The compounds of the application may be usefulfor modulating regulation of a kinase which may be involved in a normalcellular signal transduction pathway (e.g., cell growth,differentiation, survival, adhesion, migration, etc.), or a kinaseinvolved in a disease or disorder. The compounds of the application areuseful as tubulin polymerization inhibitors.

The compounds of the application are useful in treating diseases anddisorders that are modulated by tyrosine kinase inhibition. For example,the compounds of the application are useful in treating diseases anddisorders that are modulated by Src kinase. The compounds of theapplication may also be useful in treating diseases and disorders thatare modulated by focal adhesion kinase (FAK). The compounds of theapplication may also be useful in treating diseases and disorders thatare related to tubulin or tubulin polymerization.

For example, the compounds of the application may be useful asanti-proliferative agents, for treating mammals, such as for treatinghumans and animals. The compounds of the application may be used withoutlimitation, for example, as anti-cancer agents. The compounds of theapplication may be soluble in aqueous solution and in general organicsolvents.

The present application relates to a compound of formula (A):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein each of the variables in formula (A) is defined and exemplifiedherein.

In one aspect, a compound of formula (A) is a compound of any one offormula (I), (II), (III), (IVa)-(IVd), (Va)-(Vd), (VIa)-(VId), or(VIIa)-(VIIe):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein each of the variables is defined and exemplified herein.

In one aspect, the application relates to a pharmaceutical compositioncomprising a compound of the application, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof and a pharmaceuticallyacceptable carrier.

In one aspect, the application relates to a method of preventing ortreating a disease or disorder comprising administering to a subject inneed thereof an effective amount of a compound of the application, or apharmaceutically acceptable salt, solvate, or prodrug thereof, or apharmaceutical composition of the application.

In one aspect, the application relates to the use of a compound of theapplication, or a pharmaceutically acceptable salt, solvate, or prodrugthereof, or a pharmaceutical composition of the application forpreventing or treating a disease or disorder in a subject in needthereof.

In one aspect, the application relates to the use of a compound of theapplication, or a pharmaceutically acceptable salt, solvate, or prodrugthereof, or a pharmaceutical composition of the application in themanufacture of a medicament for preventing or treating a disease ordisorder in a subject in need thereof.

In one aspect, the application relates to a compound of the application,or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or apharmaceutical composition of the application for use in preventing ortreating a disease or disorder in a subject in need thereof.

The above description sets forth rather broadly the more importantfeatures of the present application in order that the detaileddescription thereof that follows may be understood, and in order thatthe present contributions to the art may be better appreciated. Otherobjects and features of the present application will become apparentfrom the following detailed description considered in conjunction withthe examples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a graph indicating the determination of the IC₅₀ for Compound121 and cisplatin in TJ905 cells. FIG. 1B is a graph indicating thedetermination of the GI₅₀ for Compound 121 and cisplatin in TJ905 cells.

FIG. 2A is a graph indicating the determination of the IC₅₀ for Compound121 and cisplatin in JEG-3 cells. FIG. 2B is a graph indicating thedetermination of the GI₅₀ for Compound 121 and cisplatin in JEG-3 cells.

FIG. 3A is a graph indicating the determination of the IC₅₀ for Compound121 and cisplatin in SW579 cells. FIG. 3B is a graph indicating thedetermination of the GI₅₀ for Compound 121 and cisplatin in SW579 cells.

FIG. 4A is a graph indicating the determination of the IC₅₀ for Compound121 and cisplatin in KYSE-150 cells. FIG. 4B is a graph indicating thedetermination of the GI₅₀ for Compound 121 and cisplatin in KYSE-150cells.

FIG. 5A is a graph indicating the determination of the IC₅₀ for Compound121 and cisplatin in 143B cells. FIG. 5B is a graph indicating thedetermination of the GI₅₀ for Compound 121 and cisplatin in 143B cells.

FIG. 6A is a graph indicating the determination of the IC₅₀ for Compound121 and cisplatin in HT-1080 cells. FIG. 6B is a graph indicating thedetermination of the GI₅₀ for Compound 121 and cisplatin in HT-1080cells.

FIG. 7A is a graph indicating the determination of the IC₅₀ for Compound121 and cisplatin in KP4 cells. FIG. 7B is a graph indicating thedetermination of the GI₅₀ for Compound 121 and cisplatin in KP4 cells.

FIG. 8A is a graph indicating the determination of the IC₅₀ for Compound121 and cisplatin in HCT-15 cells. FIG. 8B is a graph indicating thedetermination of the GI₅₀ for Compound 121 and cisplatin in HCT-15cells.

FIG. 9A is a graph indicating the determination of the IC₅₀ for Compound121 and cisplatin in SK-N-FI cells. FIG. 9B is a graph indicating thedetermination of the GI₅₀ for Compound 121 and cisplatin in SK-N-FIcells.

FIG. 10A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in HuCCT1 cells. FIG. 10B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin HuCCT1 cells.

FIG. 11A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in AsPC-1 cells. FIG. 11B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin AsPC-1 cells.

FIG. 12A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in OVCAR-3 cells. FIG. 12B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin OVCAR-3 cells.

FIG. 13A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in MDA-MB-453 cells. FIG. 13B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin MDA-MB-453 cells.

FIG. 14A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in RPMI 8226 cells. FIG. 14B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin RPMI 8226 cells.

FIG. 15A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in NCI-H226 cells. FIG. 15B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin NCI-H226 cells.

FIG. 16A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in HCT-116 cells. FIG. 16B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin HCT-116 cells.

FIG. 17A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in JHH-5 cells. FIG. 17B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin JHH-5 cells.

FIG. 18A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in A-172 cells. FIG. 18B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin A-172 cells.

FIG. 19A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in SK-OV-3 cells. FIG. 19B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin SK-OV-3 cells.

FIG. 20A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in MDA-MB-468 cells. FIG. 20B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin MDA-MB-468 cells.

FIG. 21A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in NCI-H1155 cells. FIG. 21B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin NCI-H1155 cells.

FIG. 22A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in MX-1 cells. FIG. 22B is a graph indicatingthe determination of the GI₅₀ for Compound 121 and cisplatin in MX-1cells.

FIG. 23A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in HT-1376 cells. FIG. 23B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin HT-1376 cells.

FIG. 24A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in HUH-7 cells. FIG. 24B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin HUH-7 cells.

FIG. 25A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in HeLa cells. FIG. 25B is a graph indicatingthe determination of the GI₅₀ for Compound 121 and cisplatin in HeLacells.

FIG. 26A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in K-562 cells. FIG. 26B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin K-562 cells.

FIG. 27A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in HT-29 cells. FIG. 27B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin HT-29 cells.

FIG. 28A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in NCI-H1975 cells. FIG. 28B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin NCI-H1975 cells.

FIG. 29A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in FaDu cells. FIG. 29B is a graph indicatingthe determination of the GI₅₀ for Compound 121 and cisplatin in FaDucells.

FIG. 30A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in HL-60 cells. FIG. 30B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin HL-60 cells.

FIG. 31A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in MDA-MB-231 cells. FIG. 31B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin MDA-MB-231 cells.

FIG. 32A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in 786-O cells. FIG. 32B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin 786-O cells.

FIG. 33A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in Raji cells. FIG. 33B is a graph indicatingthe determination of the GI₅₀ for Compound 121 and cisplatin in Rajicells.

FIG. 34A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in Molt-4 cells. FIG. 34B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin Molt-4 cells.

FIG. 35A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in KARPAS-299 cells. FIG. 35B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin KARPAS-299 cells.

FIG. 36A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in BT474 cells. FIG. 36B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin BT474 cells.

FIG. 37A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in NCI-H209 cells. FIG. 37B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin NCI-H209 cells.

FIG. 38A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in PC-3 cells. FIG. 38B is a graph indicatingthe determination of the GI₅₀ for Compound 121 and cisplatin in PC-3cells.

FIG. 39A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in MES-SA/DX5 cells. FIG. 39B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin MES-SA/DX5 cells.

FIG. 40A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in SK-MEL-28 cells. FIG. 40B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin SK-MEL-28 cells.

FIG. 41A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in AN3 CA cells. FIG. 41B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinAN3 CA cells.

FIG. 42A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in HuT 78 cells. FIG. 42B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin HuT 78 cells.

FIG. 43A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in 22Rv1 cells. FIG. 43B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin 22Rv1 cells.

FIG. 44A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in A2058 cells. FIG. 44B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin A2058 cells.

FIG. 45A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in SCC-4 cells. FIG. 45B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin SCC-4 cells.

FIG. 46A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in SNU-5 cells. FIG. 46B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin SNU-5 cells.

FIG. 47A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in EBC-1 cells. FIG. 47B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin EBC-1 cells.

FIG. 48A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in A-673 cells. FIG. 48B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin A-673 cells.

FIG. 49A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in U251 cells. FIG. 49B is a graph indicatingthe determination of the GI₅₀ for Compound 121 and cisplatin in U251cells.

FIG. 50A is a graph indicating the determination of the IC₅₀ forCompound 121 and cisplatin in NCI-N87 cells. FIG. 50B is a graphindicating the determination of the GI₅₀ for Compound 121 and cisplatinin NCI-N87 cells.

FIG. 51 is a graph indicating the determination of the GI₅₀ for Compound121, Compound X, and Compound Y in CCD-1106 KERTr keratinocyte cells.

FIG. 52 compares several pharmacological and physical properties ofCompound 121 and Compound Y.

FIG. 53A is a graph indicating the growth of tumors in a U87-luc humanglioblastoma subcutaneous xenograft tumor model mice dosed with vehicle.FIG. 53B is a graph indicating the growth of tumors in a U87-luc humanglioblastoma subcutaneous xenograft tumor model mice orally dosed withCompound 121. FIG. 53C is a graph indicating the effect of treatment ontime to terminal sacrifice of U87-luc human glioblastoma subcutaneousxenograft tumor model mice treated with Compound 121 compared to acontrol.

FIG. 54A is a graph indicating that Compound 121 extends survival andsupports long term tumor control in the GL261 syngeneic murine model ofhuman glioblastoma compared to Compound Y and a control. FIG. 54B is agraph indicating that Compound 121-treated mice that achieve long termsurvival (LTS) reject a sub-cutaneous challenge with GL261 cells.

DETAILED DESCRIPTION

The details of one or more embodiments of the application are set forthin the accompanying description below. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present application, the preferredmethods and materials are now described. Other features, objects, andadvantages of the application will be apparent from the description. Inthe specification, the singular forms also include the plural unless thecontext clearly dictates otherwise. Unless defined otherwise, alltechnical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisapplication belongs. In the case of conflict, the present specificationwill control.

The present application relates to a compound of formula (A):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein:

X_(a) is CR^(a) or N;

X_(b) is CR^(b) or N;

X_(c) is CR^(c) or N;

X_(d) is CR^(d) or N;

R^(a) is H, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

R^(b) is H, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

R^(c) is H, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

R^(d) is H, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

R¹ and R² are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, or O—(C₁-C₆ alkyl);

alternatively, R¹ and R², together with the carbon atom to which theyare attached, form a 3-8 membered saturated, unsaturated, or partiallysaturated carbocycle, or a saturated, unsaturated, or partiallysaturated heterocycle comprising one or two 5-7 membered rings and oneor more heteroatoms selected from N, O, and S;

alternatively, one of R¹ and R², together with the carbon atom to whichR¹ or R² is attached and

form a 7-12 membered saturated, unsaturated, or partially saturatedcarbocycle, or a 7-12 membered saturated, unsaturated, or partiallysaturated heterocycle comprising one or more heteroatoms selected fromN, O and S;

R³ and R⁴ are each independently (a) H, (b) halogen, (c) OH, (d) COOH,(e) CONH₂, (f) NHCOR¹⁰¹, (g) NR¹⁰¹COR¹⁰², (h) S(O)_(t)R¹⁰¹, (i) C₁-C₆alkyl, (j) C₂-C₆ alkenyl, (k) C₂-C₆ alkynyl, (l) O—(C₁-C₆ alkyl), (m)O—(C₂-C₆ alkenyl), (n) O—(C₂-C₆ alkynyl), (o) COO—(C₁-C₆ alkyl), (p)COO—(C₂-C₆ alkenyl), (q) COO—(C₂-C₆ alkynyl), (r) CONH—(C₁-C₆ alkyl),(s) CONH—(C₂-C₆ alkenyl), (t) CONH—(C₂-C₆ alkynyl), (u) CON(C₁-C₆alkyl)₂, (v) CON(C₂-C₆ alkenyl)₂, (w) CON(C₂-C₆ alkynyl)₂, (x) (C₁-C₆alkyl)_(u)-NH₂, (y) (C₂-C₆ alkenyl)_(u)-NH₂, (z) (C₂-C₆alkynyl)_(u)-NH₂, (aa1) (C₁-C₆ alkyl)_(v)-NH(C₁-C₆ alkyl), (aa2) (C₁-C₆alkyl)_(v)-NH(C₂-C₆ alkenyl), (aa3) (C₁-C₆ alkyl)_(v)-NH(C₂-C₆ alkynyl),(bb1) (C₂-C₆ alkenyl)_(v)-NH(C₁-C₆ alkyl), (bb2) (C₂-C₆alkenyl)_(v)-NH(C₂-C₆ alkenyl), (bb3) (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆alkynyl), (cc1) (C₂-C₆ alkynyl)_(v)-NH(C₁-C₆ alkyl), (cc2) (C₂-C₆alkynyl)_(v)-NH(C₂-C₆ alkenyl), (cc3) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆alkynyl), (dd1) (C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂, (dd2) (C₁-C₆alkyl)_(w)-N(C₂-C₆ alkenyl)₂, (dd3) (C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkynyl)₂,(ee1) (C₂-C₆ alkenyl)_(w)-N(C₁-C₆ alkyl)₂, (ee2) (C₂-C₆alkenyl)_(w)-N(C₂-C₆ alkenyl)₂, (ee3) (C₂-C₆ alkenyl)_(w)-N(C₂-C₆alkynyl)₂, (ff1) (C₂-C₆ alkynyl)_(w)-N(C₁-C₆ alkyl)₂, (ff2) (C₂-C₆alkynyl)_(w)-N(C₂-C₆ alkenyl)₂, (ff3) (C₂-C₆ alkynyl)_(w)-N(C₂-C₆alkynyl)₂, (gg) 3-8 membered saturated, unsaturated, or partiallysaturated carbocycle, or (hh) 3-8 membered saturated, unsaturated, orpartially saturated heterocycle, wherein each of (i)-(hh) is optionallysubstituted with one or more R⁷;

represents a saturated, unsaturated, or partially saturated carbocyclecomprising one or two 3-8 membered rings, or a saturated, unsaturated,or partially saturated heterocycle comprising one or two 5-8 memberedrings and one or more heteroatoms selected from N, O and S, wherein thetwo 3-8 membered rings or the two 5-8 membered rings can form a fused orbridged ring structure;

represents an aromatic, saturated, unsaturated, or partially saturatedcarbocycle comprising one or two 3-8 membered rings, or an aromatic,saturated, unsaturated, or partially saturated heterocycle comprisingone or two 5-8 membered rings and one or more heteroatoms selected fromN, O and S, wherein the two 3-8 membered rings or the two 5-8 memberedrings can form a fused or bridged ring structure;

each R⁵ is independently (a) halogen, (b) OH, (c) CONH₂, (d) COOH, (e)CN, (f) N₃, (g) C₁-C₆ alkyl, (h) C₂-C₆ alkenyl, (i) C₂-C₆ alkynyl, (j)O—(C₁-C₆ alkyl), (k) O—(C₂-C₆ alkenyl), (l) O—(C₂-C₆ alkynyl), (m)COO—(C₁-C₆ alkyl), (n) COO—(C₂-C₆ alkenyl), (o) COO—(C₂-C₆ alkynyl), (p)CONH—(C₁-C₆ alkyl), (q) CONH—(C₂-C₆ alkenyl), (r) CONH—(C₂-C₆ alkynyl),(s) CON(C₁-C₆ alkyl)₂, (t) CON(C₂-C₆ alkenyl)₂, (u) CON(C₂-C₆ alkynyl)₂,(v1) (C₁-C₆ alkyl)_(v)-NH(C₁-C₆ alkyl), (v2) (C₁-C₆ alkyl)_(v)-NH(C₂-C₆alkenyl), (v3) (C₁-C₆ alkyl)_(v)-NH(C₂-C₆ alkynyl), (w1) (C₂-C₆alkenyl)_(v)-NH(C₁-C₆ alkyl), (w2) (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆alkenyl), (w3) (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆ alkynyl), (x1) (C₂-C₆alkynyl)_(v)-NH(C₁-C₆ alkyl), (x2) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆alkenyl), (x3) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆ alkynyl), (y1) (C₁-C₆alkyl)_(w)-N(C₁-C₆ alkyl)₂, (y2) (C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkenyl)₂,(y3) (C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkynyl)₂, (z1) (C₂-C₆alkenyl)_(w)-N(C₁-C₆ alkyl)₂, (z2) (C₂-C₆ alkenyl)_(w)-N(C₂-C₆alkenyl)₂, (z3) (C₂-C₆ alkenyl)_(w)-N(C₂-C₆ alkynyl)₂, (aa1) (C₂-C₆alkynyl)_(w)-N(C₁-C₆ alkyl)₂, (aa2) (C₂-C₆ alkynyl)_(w)-N(C₂-C₆alkenyl)₂, (aa3) (C₂-C₆ alkynyl)_(w)-N(C₂-C₆ alkynyl)₂, (bb) S—(C₁-C₆alkyl), (cc) S(O)—(C₁-C₆ alkyl), (dd) S(O)₂—(C₁-C₆ alkyl), (ee) S—(C₂-C₆alkenyl), (ff) S(O)—(C₂-C₆ alkenyl), (gg) S(O)₂—(C₂-C₆ alkenyl), (hh)S—(C₂-C₆ alkynyl), (ii) S(O)—(C₂-C₆ alkynyl), (jj) S(O)₂—(C₂-C₆alkynyl), (kk) an aromatic, saturated, unsaturated, or partiallysaturated carbocycle comprising one or two 3-8 membered rings, or (ll)an aromatic, saturated, unsaturated, or partially saturated heterocyclecomprising one or two 5-7 membered rings and one or more heteroatomsselected from N, O and S, wherein each of (g)-(ll) is optionallysubstituted with one or more R⁸;

each R⁶ is independently (a) halogen, (b) OH, (c) CONH₂, (d) COOH, (e)CN, (f) N₃, (g) C₁-C₆ alkyl, (h) C₂-C₆ alkenyl, (i) C₂-C₆ alkynyl, (j)O—(C₁-C₆ alkyl), (k) O—(C₂-C₆ alkenyl), (l) O—(C₂-C₆ alkynyl), (m)COO—(C₁-C₆ alkyl), (n) COO—(C₂-C₆ alkenyl), (o) COO—(C₂-C₆ alkynyl), (p)CONH—(C₁-C₆ alkyl), (q) CONH—(C₂-C₆ alkenyl), (r) CONH—(C₂-C₆ alkynyl),(s) CON(C₁-C₆ alkyl)₂, (t) CON(C₂-C₆ alkenyl)₂, (u) CON(C₂-C₆ alkynyl)₂,(v1) (C₁-C₆ alkyl)_(v)-NH(C₁-C₆ alkyl), (v2) (C₁-C₆ alkyl)_(v)-NH(C₂-C₆alkenyl), (v3) (C₁-C₆ alkyl)_(v)-NH(C₂-C₆ alkynyl), (w1) (C₂-C₆alkenyl)_(v)-NH(C₁-C₆ alkyl), (w2) (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆alkenyl), (w3) (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆ alkynyl), (x1) (C₂-C₆alkynyl)_(v)-NH(C₁-C₆ alkyl), (x2) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆alkenyl), (x3) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆ alkynyl), (y1) (C₁-C₆alkyl)_(w)-N(C₁-C₆ alkyl)₂, (y2) (C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkenyl)₂,(y3) (C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkynyl)₂, (z1) (C₂-C₆alkenyl)_(w)-N(C₁-C₆ alkyl)₂, (z2) (C₂-C₆ alkenyl)_(w)-N(C₂-C₆alkenyl)₂, (z3) (C₂-C₆ alkenyl)_(w)-N(C₂-C₆ alkynyl)₂, (aa1) (C₂-C₆alkynyl)_(w)-N(C₁-C₆ alkyl)₂, (aa2) (C₂-C₆ alkynyl)_(w)-N(C₂-C₆alkenyl)₂, (aa3) (C₂-C₆ alkynyl)_(w)-N(C₂-C₆ alkynyl)₂, (bb) S—(C₁-C₆alkyl), (cc) S(O)—(C₁-C₆ alkyl), (dd) S(O)₂—(C₁-C₆ alkyl), (ee) S—(C₂-C₆alkenyl), (ff) S(O)—(C₂-C₆ alkenyl), (gg) S(O)₂—(C₂-C₆ alkenyl), (hh)S—(C₂-C₆ alkynyl), (ii) S(O)—(C₂-C₆ alkynyl), (jj) S(O)₂—(C₂-C₆alkynyl), (kk) an aromatic, saturated, unsaturated, or partiallysaturated carbocycle comprising one or two 3-8 membered rings, or (ll)an aromatic, saturated, unsaturated, or partially saturated heterocyclecomprising one or two 5-7 membered rings and one or more heteroatomsselected from N, O and S, wherein each of (g)-(ll) is optionallysubstituted with one or more R⁹;

each R⁷ is independently halogen, OH, O—(C₁-C₆ alkyl), COO—(C₁-C₆alkyl), CONH—(C₁-C₆ alkyl), CON(C₁-C₆ alkyl)₂, COOH, CN, N₃, 5-6membered saturated, unsaturated, or partially saturated carbocycle, or5-6 membered saturated, unsaturated, or partially saturated heterocyclecomprising one or more heteroatoms selected from N, O and S;

each R⁸ is independently halogen, OH, O—(C₁-C₆ alkyl), C₁-C₆ haloalkyl,COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl), CON(C₁-C₆ alkyl)₂, COOH, CN, N₃,5-6 membered saturated, unsaturated, or partially saturated carbocycle,or 5-6 membered saturated, unsaturated, or partially saturatedheterocycle comprising one or more heteroatoms selected from N, O and S;

each R⁹ is independently halogen, OH, O—(C₁-C₆ alkyl), COO—(C₁-C₆alkyl), CONH—(C₁-C₆ alkyl), CON(C₁-C₆ alkyl)₂, COOH, CN, N₃, 5-6membered saturated, unsaturated, or partially saturated carbocycle, or5-6 membered saturated, unsaturated, or partially saturated heterocyclecomprising one or more heteroatoms selected from N, O and S;

R¹⁰¹ and R¹⁰² are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, orC₂-C₆ alkynyl;

R¹¹ is H, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

R¹² is H, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, 4, 5, or 6;

t is 0, 1, or 2;

u is 0 or 1;

v is 0 or 1; and

w is 0 or 1,

provided that when m is 1,

is not

In one aspect, the present application relates to a compound of formula(A), wherein X_(a) is CR^(a); and X_(b) is CR^(b). In another aspect,X_(a) is CR^(a); and X_(b) is N. In another aspect, X_(a) is N; andX_(b) is CR^(b). In another aspect, X_(a) is N; and X_(b) is N.

In one aspect, the present application relates to a compound of formula(A), wherein R^(a) is H, halogen, or C₁-C₆ alkyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(a) is H. In another aspect, R^(a) is halogen (e.g., F,Cl, Br, or I). In a further aspect, R^(a) is F. In another aspect, R^(a)is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R^(a) is methyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(a) is C₂-C₆ alkenyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(a) is C₂-C₆ alkynyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(b) is H, halogen, or C₁-C₆ alkyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(b) is H. In another aspect, R^(b) is halogen (e.g., F,Cl, Br, or I). In a further aspect, R^(b) is F. In another aspect, R^(b)is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R^(b) is methyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(b) is C₂-C₆ alkenyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(b) is C₂-C₆ alkynyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(a) is H; and R^(b) is H. In another aspect, one of R^(a)and R^(b) is H, and the other is halogen (e.g., F, Cl, Br, or I) orC₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl).

In one aspect, the present application relates to a compound of formula(A), wherein X_(a) is N; X_(b) is CR^(b); and R^(b) is H. In anotheraspect, X_(b) is N; X_(a) is CR^(a); and R^(a) is H.

In one aspect, the present application relates to a compound of formula(A), wherein R¹¹ is H. In another aspect, R¹¹ is halogen (e.g., F, Cl,Br, or I). In a further aspect, R¹¹ is F. In another aspect, R¹¹ isC₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R¹¹ is methyl.

In one aspect, the present application relates to a compound of formula(A), wherein R¹² is H. In another aspect, R¹² is halogen (e.g., F, Cl,Br, or I). In a further aspect, R¹² is F. In another aspect, R¹² isC₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R¹² is methyl.

In one aspect, the present application relates to a compound of formula(A), wherein X_(a) is N; X_(b) is CR^(b); R^(b) is H; R¹¹ is methyl; andR¹² is H. In another aspect, X_(a) is N; X_(b) is CR^(b); R^(b) is H;R¹² is methyl; and R¹¹ is H. In another aspect, X_(a) is N; X_(b) isCR^(b); R^(b) is H; R¹¹ is H; and R¹² is H.

In one aspect, the present application relates to a compound of formula(A), wherein X_(b) is N; X_(a) is CR^(a); R^(a) is H; R¹¹ is methyl; andR¹² is H. In another aspect, X_(b) is N; X_(a) is CR^(a); R^(a) is H;R¹² is methyl; and R¹¹ is H. In another aspect, X_(b) is N; X_(a) isCR^(a); R^(a) is H; R¹¹ is H; and R¹² is H.

In one aspect, the present application relates to a compound of formula(A), wherein X_(c) is CR^(c); and X_(d) is CR^(d). In another aspect,X_(c) is CR^(c); and X_(d) is N. In another aspect, X_(c) is N; andX_(d) is CR^(d). In another aspect, X_(c) is N; and X_(d) is N.

In one aspect, the present application relates to a compound of formula(A), wherein R^(c) is H, halogen, or C₁-C₆ alkyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(c) is H. In another aspect, R^(c) is halogen (e.g., F,Cl, Br, or I). In a further aspect, R^(c) is F. In another aspect, R^(c)is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R^(c) is methyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(c) is C₂-C₆ alkenyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(c) is C₂-C₆ alkynyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(d) is H, halogen, or C₁-C₆ alkyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(d) is H. In another aspect, R^(d) is halogen (e.g., F,Cl, Br, or I). In a further aspect, R^(d) is F. In another aspect, R^(d)is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R^(d) is methyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(d) is C₂-C₆ alkenyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(d) is C₂-C₆ alkynyl.

In one aspect, the present application relates to a compound of formula(A), wherein R^(c) is H; and R^(d) is H. In another aspect, one of R^(c)and R^(d) is H, and the other is halogen (e.g., F, Cl, Br, or I) orC₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl).

In one aspect, the present application relates to a compound of formula(A), wherein X_(c) is CR^(c); X_(d) is CR^(d); R^(c) is H; and R^(d) isH.

In one aspect, the present application relates to a compound of formula(A), wherein X_(c) is N; X_(d) is CR^(d); and R^(d) is H. In anotheraspect, X_(d) is N; X_(c) is CR^(c); and R^(c) is H.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is (a) H, (b) halogen, (c) OH, (d) COOH, (e) CONH₂, (f)NHCOR¹⁰¹, (g) NR¹⁰¹COR¹⁰², (h) S(O)_(t)R¹⁰¹, (i) C₁-C₆ alkyl, (l)O—(C₁-C₆ alkyl), (o) COO—(C₁-C₆ alkyl), (r) CONH—(C₁-C₆ alkyl), (u)CON(C₁-C₆ alkyl)₂, (x) (C₁-C₆ alkyl)_(u)-NH₂, (aa1) (C₁-C₆alkyl)_(v)-NH(C₁-C₆ alkyl), (dd1) (C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂,(gg) 3-8 membered saturated, unsaturated, or partially saturatedcarbocycle, or (hh) 3-8 membered saturated, unsaturated, or partiallysaturated heterocycle, each of which is optionally substituted with oneor more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is 5-6 membered saturated, unsaturated, or partiallysaturated carbocycle, and is optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is H. In another aspect, R³ is halogen (e.g., F, Cl, Br,or I). In a further aspect, R³ is F. In another aspect, R³ is C₁-C₆alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, or hexyl). In a further aspect, R³ is methyl. In another aspect,R³ is OH. In another aspect, R³ is O—C₁-C₆ alkyl (e.g., methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl). In afurther aspect, R³ is O-methyl.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is COOH, CONH₂, COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, and wherein C₁-C₆ alkyl is selected from methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and hexyl, andis optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is NHCOR¹⁰¹, NR¹⁰¹COR¹⁰², or S(O)_(t)R¹⁰¹, and isoptionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is (C₁-C₆ alkyl)_(u)-NH₂, (C₁-C₆ alkyl)_(v)-NH(C₁-C₆alkyl), or (C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂, and is optionallysubstituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is 5-6 membered saturated, unsaturated, or partiallysaturated carbocycle, and is optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is C₂-C₆ alkenyl, and is optionally substituted with oneor more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is C₂-C₆ alkynyl, and is optionally substituted with oneor more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is O—(C₂-C₆ alkenyl), and is optionally substituted withone or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is O—(C₂-C₆ alkynyl), and is optionally substituted withone or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is COO—(C₂-C₆ alkenyl), CONH—(C₂-C₆ alkenyl), orCON(C₂-C₆ alkenyl)₂, and is optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is COO—(C₂-C₆ alkynyl), CONH—(C₂-C₆ alkynyl), orCON(C₂-C₆ alkynyl)₂, and is optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is (C₂-C₆ alkenyl)_(u)-NH₂, (C₁-C₆ alkyl)_(v)-NH(C₂-C₆alkenyl), (C₂-C₆ alkenyl)_(v)-NH(C₁-C₆ alkyl), (C₂-C₆alkenyl)_(v)-NH(C₂-C₆ alkenyl), (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆ alkynyl),(C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkenyl)₂, (C₂-C₆ alkenyl)_(w)-N(C₁-C₆alkyl)₂, (C₂-C₆ alkenyl)_(w)-N(C₂-C₆ alkenyl)₂, or (C₂-C₆alkenyl)_(w)-N(C₂-C₆ alkynyl)₂, and is optionally substituted with oneor more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R³ is (C₂-C₆ alkynyl)_(u)-NH₂, (C₁-C₆ alkyl)_(v)-NH(C₂-C₆alkynyl), (C₂-C₆ alkynyl)_(v)-NH(C₁-C₆ alkyl), (C₂-C₆alkynyl)_(v)-NH(C₂-C₆ alkenyl), (cc3) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆alkynyl), (C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkynyl)₂, (C₂-C₆alkynyl)_(w)-N(C₁-C₆ alkyl)₂, (C₂-C₆ alkynyl)_(w)-N(C₂-C₆ alkenyl)₂, or(C₂-C₆ alkynyl)_(w)-N(C₂-C₆ alkynyl)₂, and is optionally substitutedwith one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is (a) H, (b) halogen, (c) OH, (d) COOH, (e) CONH₂, (f)NHCOR¹⁰¹, (g) NR¹⁰¹COR¹⁰², (h) S(O)_(t)R¹⁰¹, (i) C₁-C₆ alkyl, (l)O—(C₁-C₆ alkyl), (o) COO—(C₁-C₆ alkyl), (r) CONH—(C₁-C₆ alkyl), (u)CON(C₁-C₆ alkyl)₂, (x) (C₁-C₆ alkyl)_(u)-NH₂, (aa1) (C₁-C₆alkyl)_(v)-NH(C₁-C₆ alkyl), (dd1) (C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂,(gg) 3-8 membered saturated, unsaturated, or partially saturatedcarbocycle, or (hh) 3-8 membered saturated, unsaturated, or partiallysaturated heterocycle, each of which is optionally substituted with oneor more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is 5-6 membered saturated, unsaturated, or partiallysaturated carbocycle, and is optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is H. In another aspect, R⁴ is halogen (e.g., F, Cl, Br,or I). In a further aspect, R⁴ is F. In another aspect, R⁴ is C₁-C₆alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, or hexyl). In a further aspect, R⁴ is methyl. In another aspect,R⁴ is OH. In another aspect, R⁴ is O—C₁-C₆ alkyl (e.g., methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl). In afurther aspect, R⁴ is O-methyl.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is COOH, CONH₂, COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, and wherein C₁-C₆ alkyl is selected from methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and hexyl, andis optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is NHCOR¹⁰¹, NR¹⁰¹COR¹⁰², or S(O)_(t)R¹⁰¹, and isoptionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is (C₁-C₆ alkyl)_(u)-NH₂, (C₁-C₆ alkyl)_(v)-NH(C₁-C₆alkyl), (C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂, and is optionally substitutedwith one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is 5-6 membered saturated, unsaturated, or partiallysaturated carbocycle, and is optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is C₂-C₆ alkenyl, and is optionally substituted with oneor more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is C₂-C₆ alkynyl, and is optionally substituted with oneor more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is O—(C₂-C₆ alkenyl), and is optionally substituted withone or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is O—(C₂-C₆ alkynyl), and is optionally substituted withone or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is COO—(C₂-C₆ alkenyl), CONH—(C₂-C₆ alkenyl), orCON(C₂-C₆ alkenyl)₂, and is optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is COO—(C₂-C₆ alkynyl), CONH—(C₂-C₆ alkynyl), orCON(C₂-C₆ alkynyl)₂, and is optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is (C₂-C₆ alkenyl)_(u)-NH₂, (C₁-C₆ alkyl)_(v)-NH(C₂-C₆alkenyl), (C₂-C₆ alkenyl)_(v)-NH(C₁-C₆ alkyl), (C₂-C₆alkenyl)_(v)-NH(C₂-C₆ alkenyl), (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆ alkynyl),(C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkenyl)₂, (C₂-C₆ alkenyl)_(w)-N(C₁-C₆alkyl)₂, (C₂-C₆ alkenyl)_(w)-N(C₂-C₆ alkenyl)₂, or (C₂-C₆alkenyl)_(w)-N(C₂-C₆ alkynyl)₂, and is optionally substituted with oneor more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is (C₂-C₆ alkynyl)_(u)-NH₂, (C₁-C₆ alkyl)_(v)-NH(C₂-C₆alkynyl), (C₂-C₆ alkynyl)_(v)-NH(C₁-C₆ alkyl), (C₂-C₆alkynyl)_(v)-NH(C₂-C₆ alkenyl), (cc3) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆alkynyl), (C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkynyl)₂, (C₂-C₆alkynyl)_(w)-N(C₁-C₆ alkyl)₂, (C₂-C₆ alkynyl)_(w)-N(C₂-C₆ alkenyl)₂, or(C₂-C₆ alkynyl)_(w)-N(C₂-C₆ alkynyl)₂, and is optionally substitutedwith one or more R⁷.

In one aspect, the present application relates to a compound of formula(A), wherein R⁴ is H; and R³ is H. In another aspect, R⁴ is H; and R³ ishalogen, OH, COOH, CONH₂, NHCOR¹⁰¹, NR¹⁰¹COR¹⁰², S(O)_(t)R¹⁰¹, C₁-C₆alkyl), O—(C₁-C₆ alkyl), COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, (C₁-C₆ alkyl)_(u)-NH₂, (C₁-C₆ alkyl)_(v)-NH(C₁-C₆alkyl), (C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂, or 5-6 membered saturated,unsaturated, or partially saturated carbocycle. In a further aspect, R⁴is H; and R³ is halogen (e.g., F, Cl, Br, or I), C₁-C₆ alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl), OH, or O—C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, t-butyl, pentyl, or hexyl). In a further aspect, R⁴ isH; and R³ is F, methyl, or O-methyl.

In one aspect, the present application relates to a compound of formula(A), wherein X_(c) is CR^(c); X_(d) is CR^(d); R^(c) is H; R^(d) is H;R³ is H, C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl), or O—C₁-C₆ alkyl (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl); andR⁴ is H. In a further aspect, wherein X_(c) is CR^(c); X_(d) is CR^(d);R^(c) is H; R^(d) is H; R³ is H, methyl, or O-methyl; and R⁴ is H.

In one aspect, the present application relates to a compound of formula(A), wherein R¹⁰¹ is H. In another aspect, R¹⁰¹ is C₁-C₆ alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl). In a further aspect, R¹⁰¹ is methyl.

In one aspect, the present application relates to a compound of formula(A), wherein R¹⁰² is H. In another aspect, R¹⁰² is C₁-C₆ alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl). In a further aspect, R¹⁰² is methyl.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁷ is halogen (e.g., F, Cl, Br, or I), OH, orO—(C₁-C₆ alkyl) (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, at least one R⁷ is F,OH, or O-methyl.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁷ is COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, or COOH.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁷ is CN or N₃.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁷ is 5-6 membered saturated, unsaturated, orpartially saturated carbocycle, or 5-6 membered saturated, unsaturated,or partially saturated heterocycle comprising one or more heteroatomsselected from N, O and S.

In one aspect, the present application relates to a compound of formula(A), wherein R¹ is H, C₁-C₆ alkyl, or O—(C₁-C₆ alkyl). In one aspect, R¹is H. In another aspect, R¹ is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl). In a furtheraspect, R¹ is methyl. In another aspect, R¹ is O—C₁-C₆ alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl). In a further aspect, R¹ is O-methyl.

In one aspect, the present application relates to a compound of formula(A), wherein R² is H, C₁-C₆ alkyl, or O—(C₁-C₆ alkyl). In one aspect,the present application relates to a compound of formula (A), wherein R²is H. In another aspect, R² is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl). In a furtheraspect, R² is methyl. In another aspect, R² is O—C₁-C₆ alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl). In a further aspect, R² is O-methyl.

In one aspect, the present application relates to a compound of formula(A), wherein R¹ is H; and R² is H. In another aspect, one of R¹ and R²is H, and the other is C₁-C₆ alkyl or O—(C₁-C₆ alkyl).

In one aspect, the present application relates to a compound of formula(A), wherein one of R¹ and R², together with the carbon atom to which R¹or R² is attached and

form a 7-12 membered saturated, unsaturated, or partially saturatedcarbocycle. In a further aspect, one of R¹ and R², together with thecarbon atom to which R¹ or R² is attached and

form a dihydroindene. In one aspect, the present application relates toa compound of formula (A), wherein one of R¹ and R², together with thecarbon atom to which R¹ or R² is attached and

form a 7-12 membered saturated, unsaturated, or partially saturatedheterocycle comprising one or more heteroatoms selected from N, O and S.

In one aspect, the present application relates to a compound of formula(A), wherein R¹ and R², together with the carbon atom to which they areattached, form a 3-8 membered saturated, unsaturated, or partiallysaturated carbocycle.

In one aspect, the present application relates to a compound of formula(A), wherein R¹ and R², together with the carbon atom to which they areattached, form a saturated, unsaturated, or partially saturatedheterocycle comprising one or two 5-7 membered rings and one or moreheteroatoms selected from N, O, and S

In one aspect, the present application relates to a compound of formula(A), wherein

represents a saturated, unsaturated, or partially saturated carbocyclecomprising one or two 3-8 membered rings, wherein the two 3-8 memberedrings can form a fused or bridged ring structure.

In one aspect, the present application relates to a compound of formula(A), wherein

represents a saturated, unsaturated, or partially saturated heterocyclecomprising one or two 5-8 membered rings and one or more heteroatomsselected from N, O and S, wherein the two 5-8 membered rings can form afused or bridged ring structure.

In one aspect, the present application relates to a compound of formula(A), wherein

represents a 5-6 membered saturated, unsaturated, or partially saturatedcarbocycle. In another aspect,

represents a saturated, unsaturated, or partially saturated heterocyclecomprising one or more heteroatoms selected from N, O and S. In afurther aspect,

represents a saturated heterocycle comprising one or more heteroatomsselected from N, O and S, and is optionally substituted. In a furtheraspect, the heterocycle comprises a two-ring bridged ring system. In afurther aspect,

represents an optionally substituted heterocycle selected from:

In a further aspect,

represents

In one aspect, the present application relates to a compound of formula(A), wherein m is 1. In another aspect, m is 2. In another aspect, m is3. In another aspect, m is 4. In another aspect, m is 5. In anotheraspect, m is 6.

In one aspect, the present application relates to a compound of formula(A), wherein R⁵ is (a) halogen, (b) OH, (c) CONH₂, (d) COOH, (e) CN, (f)N₃, (g) C₁-C₆ alkyl, (h) C₂-C₆ alkenyl, (j) O—(C₁-C₆ alkyl), (m)COO—(C₁-C₆ alkyl), (p) CONH—(C₁-C₆ alkyl), or (s) CON(C₁-C₆ alkyl)₂,each of which is optionally substituted with one or more R⁸.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is halogen (e.g., F, Cl, Br, or I). In afurther aspect, at least one R⁵ is F. In another aspect, at least one R⁵is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, at least one R⁵ ismethyl. In another aspect, at least one R⁵ is OH, CN, or N₃. In anotheraspect, at least one R⁵ is O—C₁-C₆ alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl). In a furtheraspect, at least one R⁵ is O-methyl.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is C₂-C₆ alkenyl.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is C₂-C₆ alkynyl.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, CONH₂, or COOH.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is CN.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is N₃.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is O—(C₂-C₆ alkenyl).

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is O—(C₂-C₆ alkynyl).

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is COO—(C₂-C₆ alkenyl), CONH—(C₂-C₆alkenyl), or CON(C₂-C₆ alkenyl)₂.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is COO—(C₂-C₆ alkynyl), CONH—(C₂-C₆alkynyl), or CON(C₂-C₆ alkynyl)₂.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is (C₁-C₆ alkyl)_(v)-NH(C₁-C₆ alkyl), or(C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is (C₁-C₆ alkyl)_(v)-NH(C₂-C₆ alkenyl),(C₂-C₆ alkenyl)_(v)-NH(C₁-C₆ alkyl), (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆alkenyl), (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆ alkynyl), (C₁-C₆alkyl)_(w)-N(C₂-C₆ alkenyl)₂, (C₂-C₆ alkenyl)_(w)-N(C₁-C₆ alkyl)₂,(C₂-C₆ alkenyl)_(w)-N(C₂-C₆ alkenyl)₂, or (C₂-C₆ alkenyl)_(w)-N(C₂-C₆alkynyl)₂.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is (C₁-C₆ alkyl)_(v)-NH(C₂-C₆ alkynyl),(C₂-C₆ alkynyl)_(v)-NH(C₁-C₆ alkyl), (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆alkenyl), (cc3) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆ alkynyl), (C₁-C₆alkyl)_(w)-N(C₂-C₆ alkynyl)₂, (C₂-C₆ alkynyl)_(w)-N(C₁-C₆ alkyl)₂,(C₂-C₆ alkynyl)_(w)-N(C₂-C₆ alkenyl)₂, (C₂-C₆ alkynyl)_(w)-N(C₂-C₆alkynyl)₂.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is S(O)—(C₂-C₆ alkenyl), S(O)₂—(C₂-C₆alkenyl), S—(C₂-C₆ alkynyl), S(O)—(C₂-C₆ alkynyl), or S(O)₂—(C₂-C₆alkynyl).

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁵ is an aromatic, saturated, unsaturated, orpartially saturated carbocycle comprising one or two 3-8 membered rings,or an aromatic, saturated, unsaturated, or partially saturatedheterocycle comprising one or two 5-7 membered rings and one or moreheteroatoms selected from N, O and S.

In one aspect, the present application relates to a compound of formula(A), wherein R⁵ is in the S-configuration.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁸ is halogen (e.g., F, Cl, Br, or I), OH,O—(C₁-C₆ alkyl) (e.g., methyl, ethyl, propyl, propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl), or C₁-C₆ haloalkyl (e.g., CHF₂, CH₂F, CF₃,CH₂CHF₂, CH₂CH₂F, or CH₂CF₃). In a further aspect, at least one R⁸ is F,OH, O-methyl, or CF₃.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁸ is COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, or COOH.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁸ is CN or N₃.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁸ is 5-6 membered saturated, unsaturated, orpartially saturated carbocycle, or 5-6 membered saturated, unsaturated,or partially saturated heterocycle comprising one or more heteroatomsselected from N, O and S.

In one aspect, the present application relates to a compound of formula(A), wherein

represents a saturated, unsaturated, or partially saturated carbocyclecomprising one or two 3-8 membered rings, wherein the two 3-8 memberedrings can form a fused or bridged ring structure.

In one aspect, the present application relates to a compound of formula(A), wherein

represents a saturated, unsaturated, or partially saturated heterocyclecomprising one or two 5-8 membered rings and one or more heteroatomsselected from N, O and S, wherein the two 5-8 membered rings can form afused or bridged ring structure.

In one aspect, the present application relates to a compound of formula(A), wherein

represents a 5-6 membered aromatic, saturated, unsaturated, or partiallysaturated carbocycle. In a further aspect,

represents a 6 membered aromatic carbocycle (e.g., phenyl). In a furtheraspect,

represents phenyl.

In one aspect, the present application relates to a compound of formula(A), wherein

represents an aromatic, saturated, unsaturated, or partially saturatedheterocycle comprising one or more heteroatoms selected from N, O and S.In a further aspect,

represents an aromatic heterocycle comprising one or more heteroatomsselected from N, O and S (e.g., pyridine, pyrazine, or pyrimidine). In afurther aspect,

represents pyridine.

In one aspect, the present application relates to a compound of formula(A), wherein n is 0. In another aspect, n is 1, 2, 3, 4, 5, or 6. In afurther aspect, n is 1.

In one aspect, the present application relates to a compound of formula(A), wherein R⁶ is (a) halogen, (b) OH, (c) CONH₂, (d) COOH, (e) CN, (f)N₃, (g) C₁-C₆ alkyl, (h) C₂-C₆ alkenyl, (j) O—(C₁-C₆ alkyl), (m)COO—(C₁-C₆ alkyl), (p) CONH—(C₁-C₆ alkyl), or (s) CON(C₁-C₆ alkyl)₂,each of which is optionally substituted with one or more R⁹.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is halogen (e.g., F, Cl, Br, or I). In afurther aspect, at least one R⁶ is F. In a further aspect, R⁶ is2-fluoro or 4-fluoro. In a further aspect, R⁶ is 2-fluoro. In a furtheraspect, R⁶ is 4-fluoro. In another aspect, at least one R⁶ is C₁-C₆alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, or hexyl). In a further aspect, at least one R⁶ is methyl. Inanother aspect, at least one R⁶ is OH. In another aspect, at least oneR⁶ is O—C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl). In a further aspect, at least oneR⁶ is O-methyl.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is C₂-C₆ alkenyl.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is C₂-C₆ alkynyl.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, CONH₂, or COOH.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is CN.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is N₃.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is O—(C₂-C₆ alkenyl).

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is O—(C₂-C₆ alkynyl).

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is COO—(C₂-C₆ alkenyl), CONH—(C₂-C₆alkenyl), or CON(C₂-C₆ alkenyl)₂.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is COO—(C₂-C₆ alkynyl), CONH—(C₂-C₆alkynyl), or CON(C₂-C₆ alkynyl)₂.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is (C₁-C₆ alkyl)_(v)-NH(C₁-C₆ alkyl), or(C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is (C₁-C₆ alkyl)_(v)-NH(C₂-C₆ alkenyl),(C₂-C₆ alkenyl)_(v)-NH(C₁-C₆ alkyl), (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆alkenyl), (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆ alkynyl), (C₁-C₆alkyl)_(w)-N(C₂-C₆ alkenyl)₂, (C₂-C₆ alkenyl)_(w)-N(C₁-C₆ alkyl)₂,(C₂-C₆ alkenyl)_(w)-N(C₂-C₆ alkenyl)₂, or (C₂-C₆ alkenyl)_(w)-N(C₂-C₆alkynyl)₂.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is (C₁-C₆ alkyl)_(v)-NH(C₂-C₆ alkynyl),(C₂-C₆ alkynyl)_(v)-NH(C₁-C₆ alkyl), (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆alkenyl), (cc3) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆ alkynyl), (C₁-C₆alkyl)_(w)-N(C₂-C₆ alkynyl)₂, (C₂-C₆ alkynyl)_(w)-N(C₁-C₆ alkyl)₂,(C₂-C₆ alkynyl)_(w)-N(C₂-C₆ alkenyl)₂, (C₂-C₆ alkynyl)_(w)-N(C₂-C₆alkynyl)₂.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is S(O)—(C₂-C₆ alkenyl), S(O)₂—(C₂-C₆alkenyl), S—(C₂-C₆ alkynyl), S(O)—(C₂-C₆ alkynyl), or S(O)₂—(C₂-C₆alkynyl).

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is an aromatic, saturated, unsaturated, orpartially saturated carbocycle comprising one or two 3-8 membered rings,or an aromatic, saturated, unsaturated, or partially saturatedheterocycle comprising one or two 5-7 membered rings and one or moreheteroatoms selected from N, O and S.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁶ is bonded to the 2- or 4-position of

In a further aspect, at least one R⁶ is 2-F, 2-methyl, 2-OH, 2-O-methyl,2-CN, or 2-N₃. In another aspect, at least one R⁶ is 4-F, 4-methyl,4-OH, 4-O-methyl, 4-CN, or 4-N₃. In a further aspect,

is phenyl or pyridine; and at least one R⁶ is 2-F, 2-methyl, 2-OH,2-O-methyl, 2-CN, or 2-N₃. In another aspect,

is phenyl or pyridine; and at least one R⁶ is 4-F, 4-methyl, 4-OH,4-O-methyl, 4-CN, or 4-N₃.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁹ is halogen (e.g., F, Cl, Br, or I), OH, orO—(C₁-C₆ alkyl) (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, at least one R⁹ is F,OH, or O-methyl.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁹ is COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, or COOH.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁹ is CN or N₃.

In one aspect, the present application relates to a compound of formula(A), wherein at least one R⁹ is 5-6 membered saturated, unsaturated, orpartially saturated carbocycle, or 5-6 membered saturated, unsaturated,or partially saturated heterocycle comprising one or more heteroatomsselected from N, O and S.

The present application relates to a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein:

X_(a) is CR^(a) or N;

X_(b) is CR^(b) or N;

X_(c) is CR^(c) or N;

X_(d) is CR^(d) or N;

R^(a) is H, halogen, or C₁-C₆ alkyl;

R^(b) is H, halogen, or C₁-C₆ alkyl;

R^(c) is H, halogen, or C₁-C₆ alkyl;

R^(d) is H, halogen, or C₁-C₆ alkyl;

R¹ and R² are each independently H, C₁-C₆ alkyl, or O—(C₁-C₆ alkyl);

alternatively, one of R¹ and R², together with the carbon atom to whichR¹ or R² is attached and

form a 7-12 membered saturated, unsaturated, or partially saturatedcarbocycle, or a 7-12 membered saturated, unsaturated, or partiallysaturated heterocycle containing one or more heteroatoms selected fromN, O and S;

R³ and R⁴ are each independently (a) H, (b) halogen, (c) OH, (d) COOH,(e) CONH₂, (f) NHCOR¹⁰¹, (g) NR¹⁰¹COR¹⁰², (h) S(O)_(t)R¹⁰¹, (i) C₁-C₆alkyl, (j) O—(C₁-C₆ alkyl), (k) COO—(C₁-C₆ alkyl), (l) CONH—(C₁-C₆alkyl), (m) CON(C₁-C₆ alkyl)₂, (n) (C₁-C₆ alkyl)_(u)-NH₂, (o) (C₁-C₆alkyl)_(v)-NH(C₁-C₆ alkyl), (p) (C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂, or(q) 5-6 membered saturated, unsaturated, or partially saturatedcarbocycle, wherein each of (i)-(q) is optionally substituted with oneor more R⁷;

represents a 5-6 membered saturated, unsaturated, or partially saturatedcarbocycle, or a 5-6 membered saturated, unsaturated, or partiallysaturated heterocycle containing one or more heteroatoms selected fromN, O and S;

represents a 5-6 membered aromatic, saturated, unsaturated, or partiallysaturated carbocycle, or a 5-6 membered aromatic, saturated,unsaturated, or partially saturated heterocycle containing one or moreheteroatoms selected from N, O and S;

each R⁵ is independently (a) halogen, (b) OH, (c) C₁-C₆ alkyl, (d) C₂-C₆alkenyl, (e) O—(C₁-C₆ alkyl), (f) COO—(C₁-C₆ alkyl), (g) CONH—(C₁-C₆alkyl), (h) CON(C₁-C₆ alkyl)₂, (i) COOH, (j) CN, or (k) N₃, wherein eachof (c)-(h) is optionally substituted with one or more R⁸;

each R⁶ is independently (a) halogen, (b) OH, (c) C₁-C₆ alkyl, (d) C₂-C₆alkenyl, (e) O—(C₁-C₆ alkyl), (f) COO—(C₁-C₆ alkyl), (g) CONH—(C₁-C₆alkyl), (h) CON(C₁-C₆ alkyl)₂, (i) COOH, (j) CN, or (k) N₃, wherein eachof (c)-(h) is optionally substituted with one or more R⁹;

each R⁷ is independently halogen, OH, O—(C₁-C₆ alkyl), COO—(C₁-C₆alkyl), CONH—(C₁-C₆ alkyl), CON(C₁-C₆ alkyl)₂, COOH, CN, N₃, 5-6membered saturated, unsaturated, or partially saturated carbocycle, or5-6 membered saturated, unsaturated, or partially saturated heterocyclecontaining one or more heteroatoms selected from N, O and S;

each R⁸ is independently halogen, OH, O—(C₁-C₆ alkyl), C₁-C₆ haloalkyl,COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl), CON(C₁-C₆ alkyl)₂, COOH, CN, N₃,5-6 membered saturated, unsaturated, or partially saturated carbocycle,or 5-6 membered saturated, unsaturated, or partially saturatedheterocycle containing one or more heteroatoms selected from N, O and S;

each R⁹ is independently halogen, OH, O—(C₁-C₆ alkyl), COO—(C₁-C₆alkyl), CONH—(C₁-C₆ alkyl), CON(C₁-C₆ alkyl)₂, COOH, CN, N₃, 5-6membered saturated, unsaturated, or partially saturated carbocycle, or5-6 membered saturated, unsaturated, or partially saturated heterocyclecontaining one or more heteroatoms selected from N, O and S;

R¹⁰¹ and R¹⁰² are each independently H or C₁-C₆ alkyl;

R¹¹ is H, halogen, or C₁-C₆ alkyl;

R¹² is H, halogen, or C₁-C₆ alkyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, 4, 5, or 6;

t is 0, 1, or 2;

u is 0 or 1;

v is 0 or 1; and

w is 0 or 1,

provided that when m is 1,

is not

In one aspect, the present application relates to a compound of formula(I), wherein X_(a) is CR^(a); and X_(b) is CR^(b). In another aspect,X_(a) is CR^(a); and X_(b) is N. In another aspect, X_(a) is N; andX_(b) is CR^(b). In another aspect, X_(a) is N; and X_(b) is N.

In one aspect, the present application relates to a compound of formula(I), wherein R^(a) is H. In another aspect, R^(a) is halogen (e.g., F,Cl, Br, or I). In a further aspect, R^(a) is F. In another aspect, R^(a)is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R^(a) is methyl.

In one aspect, the present application relates to a compound of formula(I), wherein R^(b) is H. In another aspect, R^(b) is halogen (e.g., F,Cl, Br, or I). In a further aspect, R^(b) is F. In another aspect, R^(b)is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R^(b) is methyl.

In one aspect, the present application relates to a compound of formula(I), wherein R^(a) is H; and R^(b) is H. In another aspect, one of R^(a)and R^(b) is H, and the other is halogen (e.g., F, Cl, Br, or I) orC₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl).

In one aspect, the present application relates to a compound of formula(I), wherein X_(a) is N; X_(b) is CR^(b); and R^(b) is H. In anotheraspect, X_(b) is N; X_(a) is CR^(a); and R^(a) is H.

In one aspect, the present application relates to a compound of formula(I), wherein R¹¹ is H. In another aspect, R¹¹ is halogen (e.g., F, Cl,Br, or I). In a further aspect, R¹¹ is F. In another aspect, R¹¹ isC₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R¹¹ is methyl.

In one aspect, the present application relates to a compound of formula(I), wherein R¹² is H. In another aspect, R¹² is halogen (e.g., F, Cl,Br, or I). In a further aspect, R¹² is F. In another aspect, R¹² isC₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R¹² is methyl.

In one aspect, the present application relates to a compound of formula(I), wherein X_(a) is N; X_(b) is CR^(b); R^(b) is H; R¹¹ is methyl; andR¹² is H. In another aspect, X_(a) is N; X_(b) is CR^(b); R^(b) is H;R¹² is methyl; and R¹¹ is H. In another aspect, X_(a) is N; X_(b) isCR^(b); R^(b) is H; R¹¹ is H; and R¹² is H.

In one aspect, the present application relates to a compound of formula(I), wherein X_(b) is N; X_(a) is CR^(a); R^(a) is H; R¹¹ is methyl; andR¹² is H. In another aspect, X_(b) is N; X_(a) is CR^(a); R^(a) is H;R¹² is methyl; and R¹¹ is H. In another aspect, X_(b) is N; X_(a) isCR^(a); R^(a) is H; R¹¹ is H; and R¹² is H.

In one aspect, the present application relates to a compound of formula(I), wherein X_(c) is CR^(c); and X_(d) is CR^(d). In another aspect,X_(c) is CR^(c); and X_(d) is N. In another aspect, X_(c) is N; andX_(d) is CR^(d). In another aspect, X_(c) is N; and X_(d) is N.

In one aspect, the present application relates to a compound of formula(I), wherein R^(c) is H. In another aspect, R^(c) is halogen (e.g., F,Cl, Br, or I). In a further aspect, R^(c) is F. In another aspect, R^(c)is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R^(c) is methyl.

In one aspect, the present application relates to a compound of formula(I), wherein R^(d) is H. In another aspect, R^(d) is halogen (e.g., F,Cl, Br, or I). In a further aspect, R^(d) is F. In another aspect, R^(d)is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R^(d) is methyl.

In one aspect, the present application relates to a compound of formula(I), wherein R^(c) is H; and R^(d) is H. In another aspect, one of R^(c)and R^(d) is H, and the other is halogen (e.g., F, Cl, Br, or I) orC₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl).

In one aspect, the present application relates to a compound of formula(I), wherein X_(c) is CR^(c); X_(d) is CR^(d); R^(c) is H; and R^(d) isH.

In one aspect, the present application relates to a compound of formula(I), wherein X_(c) is N; X_(d) is CR^(d); and R^(d) is H. In anotheraspect, X_(d) is N; X_(c) is CR^(c); and R^(c) is H.

In one aspect, the present application relates to a compound of formula(I), wherein R³ is H. In another aspect, R³ is halogen (e.g., F, Cl, Br,or I). In a further aspect, R³ is F. In another aspect, R³ is C₁-C₆alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, or hexyl). In a further aspect, R³ is methyl. In another aspect,R³ is OH. In another aspect, R³ is O—C₁-C₆ alkyl (e.g., methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl). In afurther aspect, R³ is O-methyl.

In one aspect, the present application relates to a compound of formula(I), wherein R³ is COOH, CONH₂, COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, and wherein C₁-C₆ alkyl is selected from methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and hexyl, andis optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(I), wherein R³ is NHCOR¹⁰¹, NR¹⁰¹COR¹⁰², or S(O)_(t)R¹⁰¹, and isoptionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(I), wherein R³ is (C₁-C₆ alkyl)_(u)-NH₂, (C₁-C₆ alkyl)_(v)-NH(C₁-C₆alkyl), (C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂, and is optionally substitutedwith one or more R⁷.

In one aspect, the present application relates to a compound of formula(I), wherein R³ is 5-6 membered saturated, unsaturated, or partiallysaturated carbocycle, and is optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(I), wherein R⁴ is H. In another aspect, R⁴ is halogen (e.g., F, Cl, Br,or I). In a further aspect, R⁴ is F. In another aspect, R⁴ is C₁-C₆alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, or hexyl). In a further aspect, R⁴ is methyl. In another aspect,R⁴ is OH. In another aspect, R⁴ is O—C₁-C₆ alkyl (e.g., methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl). In afurther aspect, R⁴ is O-methyl.

In one aspect, the present application relates to a compound of formula(I), wherein R⁴ is COOH, CONH₂, COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, and wherein C₁-C₆ alkyl is selected from methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and hexyl, andis optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(I), wherein R⁴ is NHCOR¹⁰¹, NR¹⁰¹COR¹⁰², or S(O)_(t)R¹⁰¹, and isoptionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(I), wherein R⁴ is (C₁-C₆ alkyl)_(u)-NH₂, (C₁-C₆ alkyl)_(v)NH(C₁-C₆alkyl), (C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂, and is optionally substitutedwith one or more R⁷.

In one aspect, the present application relates to a compound of formula(I), wherein R⁴ is 5-6 membered saturated, unsaturated, or partiallysaturated carbocycle, and is optionally substituted with one or more R⁷.

In one aspect, the present application relates to a compound of formula(I), wherein R⁴ is H; and R³ is H. In another aspect, R⁴ is H; and R³ ishalogen, OH, COOH, CONH₂, NHCOR¹⁰¹, NR¹⁰¹COR¹⁰², S(O)_(t)R¹⁰¹, C₁-C₆alkyl, O—(C₁-C₆ alkyl), COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl), CON(C₁-C₆alkyl)₂, (C₁-C₆ alkyl)_(u)-NH₂, (C₁-C₆ alkyl)_(v)-NH(C₁-C₆ alkyl),(C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂, or 5-6 membered saturated,unsaturated, or partially saturated carbocycle. In a further aspect, R⁴is H; and R³ is halogen (e.g., F, Cl, Br, or I), C₁-C₆ alkyl (e.g.,methyl, ethyl, propyl, propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl), OH, or O—C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, t-butyl, pentyl, or hexyl). In a further aspect, R⁴ isH; and R³ is F, methyl, or O-methyl.

In one aspect, the present application relates to a compound of formula(I), wherein X_(c) is CR^(c); X_(d) is CR^(d); R^(c) is H; R^(d) is H;R³ is H, C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl), or O—C₁-C₆ alkyl (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl); andR⁴ is H. In a further aspect, wherein X_(c) is CR^(c); X_(d) is CR^(d);R^(c) is H; R^(d) is H; R³ is H, methyl, or O-methyl; and R⁴ is H.

In one aspect, the present application relates to a compound of formula(I), wherein R¹⁰¹ is H. In another aspect, R¹⁰¹ is C₁-C₆ alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl). In a further aspect, R¹⁰¹ is methyl.

In one aspect, the present application relates to a compound of formula(I), wherein R¹⁰² is H. In another aspect, R¹⁰² is C₁-C₆ alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl). In a further aspect, R¹⁰² is methyl.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁷ is halogen (e.g., F, Cl, Br, or I), OH, orO—(C₁-C₆ alkyl) (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, at least one IC is F,OH, or O-methyl.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁷ is COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, or COOH.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁷ is CN or N₃.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁷ is 5-6 membered saturated, unsaturated, orpartially saturated carbocycle, or 5-6 membered saturated, unsaturated,or partially saturated heterocycle containing one or more heteroatomsselected from N, O and S.

In one aspect, the present application relates to a compound of formula(I), wherein R¹ is H. In another aspect, R¹ is C₁-C₆ alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl). In a further aspect, R¹ is methyl. In another aspect, R¹ isO—C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R¹ is O-methyl.

In one aspect, the present application relates to a compound of formula(I), wherein R² is H. In another aspect, R² is C₁-C₆ alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl). In a further aspect, R² is methyl. In another aspect, R² isO—C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, R² is O-methyl.

In one aspect, the present application relates to a compound of formula(I), wherein R¹ is H; and R² is H. In another aspect, one of R¹ and R²is H, and the other is C₁-C₆ alkyl or O—(C₁-C₆ alkyl).

In one aspect, the present application relates to a compound of formula(I), wherein one of R¹ and R², together with the carbon atom to which R¹or R² is attached and

form a 7-12 membered saturated, unsaturated, or partially saturatedcarbocycle. In a further aspect, one of R¹ and R², together with thecarbon atom to which R¹ or R² is attached and

form a dihydroindene, i.e., indane or benzocyclopentane. In one aspect,the present application relates to a compound of formula (I), whereinone of R¹ and R², together with the carbon atom to which R¹ or R² isattached and

form a 7-12 membered saturated, unsaturated, or partially saturatedheterocycle containing one or more heteroatoms selected from N, O and S.

In one aspect, the present application relates to a compound of formula(I), wherein

represents a 5-6 membered saturated, unsaturated, or partially saturatedcarbocycle. In another aspect,

represents a saturated, unsaturated, or partially saturated heterocyclecontaining one or more heteroatoms selected from N, O and S. In afurther aspect,

represents a saturated heterocycle containing one or more heteroatomsselected from N, O and S, and is optionally substituted. In a furtheraspect, the heterocycle comprises a two-ring bridged ring system. In afurther aspect,

represents an optionally substituted heterocycle selected from:

In a further aspect,

represents

In one aspect, the present application relates to a compound of formula(I), wherein m is 1. In another aspect, m is 2. In another aspect, m is3. In another aspect, m is 4. In another aspect, m is 5. In anotheraspect, m is 6.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁵ is halogen (e.g., F, Cl, Br, or I). In afurther aspect, at least one R⁵ is F. In another aspect, at least one R⁵is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, at least one R⁵ ismethyl. In another aspect, at least one R⁵ is OH, CN, or N₃. In anotheraspect, at least one R⁵ is O—C₁-C₆ alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl). In a furtheraspect, at least one R⁵ is O-methyl.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁵ is C₂-C₆ alkenyl.

In one aspect, the present application relates to a compound of formula(I), wherein R⁵ is in the S-configuration.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁵ is COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, or COOH.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁸ is halogen (e.g., F, Cl, Br, or I), OH,O—(C₁-C₆ alkyl) (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl), or C₁-C₆ haloalkyl (e.g., CHF₂, CH₂F, CF₃,CH₂CHF₂, CH₂CH₂F, or CH₂CF₃). In a further aspect, at least one R⁸ is F,OH, O-methyl, or CF₃.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁸ is COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, or COOH.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁸ is CN or N₃.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁸ is 5-6 membered saturated, unsaturated, orpartially saturated carbocycle, or 5-6 membered saturated, unsaturated,or partially saturated heterocycle containing one or more heteroatomsselected from N, O and S.

In one aspect, the present application relates to a compound of formula(I), wherein

represents a 5-6 membered aromatic, saturated, unsaturated, or partiallysaturated carbocycle. In a further aspect,

represents a 6 membered aromatic carbocycle (e.g., phenyl). In a furtheraspect,

represents phenyl.

In one aspect, the present application relates to a compound of formula(I), wherein

represents an aromatic, saturated, unsaturated, or partially saturatedheterocycle containing one or more heteroatoms selected from N, O and S.In a further aspect,

represents an aromatic heterocycle containing one or more heteroatomsselected from N, O and S (e.g., pyridine, pyrazine, or pyrimidine). In afurther aspect,

represents pyridine.

In one aspect, the present application relates to a compound of formula(I), wherein n is 0. In another aspect, n is 1, 2, 3, 4, 5, or 6. In afurther aspect, n is 1.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁶ is halogen (e.g., F, Cl, Br, or I). In afurther aspect, at least one R⁶ is F. In a further aspect, R⁶ is2-fluoro or 4-fluoro. In a further aspect, R⁶ is 2-fluoro. In a furtheraspect, R⁶ is 4-fluoro. In another aspect, at least one R⁶ is C₁-C₆alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, or hexyl). In a further aspect, at least one R⁶ is methyl. Inanother aspect, at least one R⁶ is OH. In another aspect, at least oneR⁶ is O—C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl). In a further aspect, at least oneR⁶ is O-methyl.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁶ is C₂-C₆ alkenyl.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁶ is COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, or COOH.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁶ is CN.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁶ is N₃.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁶ is bonded to the 2- or 4-position of

In a further aspect, at least one R⁶ is 2-F, 2-methyl, 2-OH, 2-O-methyl,2-CN, or 2-N₃. In another aspect, at least one R⁶ is 4-F, 4-methyl,4-OH, 4-O-methyl, 4-CN, or 4-N₃. In a further aspect,

is phenyl or pyridine; and at least one R⁶ is 2-F, 2-methyl, 2-OH,2-O-methyl, 2-CN, or 2-N₃. In another aspect,

is phenyl or pyridine; and at least one R⁶ is 4-F, 4-methyl, 4-OH,4-O-methyl, 4-CN, or 4-N₃.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁹ is halogen (e.g., F, Cl, Br, or I), OH, orO—(C₁-C₆ alkyl) (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl). In a further aspect, at least one R⁹ is F,OH, or O-methyl.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁹ is COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, or COOH.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁹ is CN or N₃.

In one aspect, the present application relates to a compound of formula(I), wherein at least one R⁹ is 5-6 membered saturated, unsaturated, orpartially saturated carbocycle, or 5-6 membered saturated, unsaturated,or partially saturated heterocycle containing one or more heteroatomsselected from N, O and S.

In one aspect, the present application relates to a compound of formula(I), wherein at least one of R³, R⁴, R¹¹, or R¹² is methyl. In a furtheraspect, one of R³, R⁴, R¹¹, or R¹² is methyl.

In one aspect, the present application relates to a compound of formula(I), wherein at R³ is methyl and R⁴, R¹¹ and R¹² are H.

In one aspect, the present application relates to a compound of formula(I), wherein at R⁴ is methyl and R³, R¹¹, and R¹² are H.

In one aspect, the present application relates to a compound of formula(I), wherein at R¹¹ is methyl and R³, R⁴, and R¹² are H.

In one aspect, the present application relates to a compound of formula(I), wherein at R¹² is methyl and R³, R⁴, and R¹¹ are H.

In one aspect, the present application relates to a compound of formula(I), wherein at least one of R³, R⁴, R¹¹, or R¹² is O-methyl. In afurther aspect, one of R³, R⁴, R¹¹, or R¹² is O-methyl.

In one aspect, the present application relates to a compound of formula(I), wherein at R³ is O-methyl and R⁴, R¹¹, and R¹² are H.

In one aspect, the present application relates to a compound of formula(I), wherein at R⁴ is O-methyl and R³, R¹¹, and R¹² are H.

In one aspect, the present application relates to a compound of formula(I), wherein at R¹¹ is O-methyl and R³, R⁴, and R¹² are H.

In one aspect, the present application relates to a compound of formula(I), wherein at R¹² is O-methyl and R³, R⁴, and R¹¹ are H.

In one aspect, the present application relates to a compound of formula(II):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein each of the variables is as defined in formula (I). In a furtheraspect,

R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², m, and n are selected from themoieties described herein.

In one aspect, the present application relates to a compound of formula(III):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein each of

R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², and m is as defined in formula (I),and n1 is 0, 1, 2, 3, 4, or 5. In a further aspect,

R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², and m are selected from the moietiesdescribed herein. In a further aspect, n1 is 0. In another aspect, n1 is1.

In one aspect, the present application relates to a compound of aformula selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein each of R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², and m is as defined informula (I); R⁵¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, O—(C₁-C₆ alkyl),COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl), CON(C₁-C₆ alkyl)₂, or CN, each ofwhich is optionally substituted with one or more R⁸; and m1 is 0, 1, 2,3, or 4. In a further aspect, R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², and mare selected from the moieties described herein. In a further aspect, m1is 0. In another aspect, m1 is 1. In a further aspect, each of thesubstituents defined for R⁵¹ can be selected from the moieties describedherein for the corresponding substituent defined for R⁵.

In one aspect, the present application relates to a compound of aformula selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein each of the variables is as defined in formula (I). In a furtheraspect, R¹, R², R⁵, and R⁶ are selected from the moieties describedherein.

In one aspect, the present application relates to a compound of aformula selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein each of the variables is as defined in formula (I). In a furtheraspect, R¹, R², R⁵, and R⁶ are selected from the moieties describedherein.

In one aspect, the present application relates to a compound of formula(VIIa), (VIIb), (VIIc), (VIId), or (VIIe):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein each of R¹, R², R³, R⁵, and R⁶ is as defined in formula (I); n2is 0, 1, 2, or 3; n3 is 0, 1, or 2; A¹, A², and A³ are eachindependently CR⁶¹ or N, wherein only one of A¹, A², and A³ is N; andeach R⁶¹ is independently H or R⁶. In a further aspect, R¹, R², R³, R⁵,and R⁶ are selected from the moieties described herein.

In one aspect, R³ is H, methyl, or O-methyl. In a further aspect, R³ ismethyl or O-methyl. In a further aspect, R³ is methyl.

In one aspect, R⁵ is methyl.

In one aspect, R⁵ is in the S-configuration.

In one aspect, n2 is 0. In another aspect, n2 is 1.

In one aspect, n3 is 0. In another aspect, n3 is 1.

In one aspect, R⁶ is halogen, C₁-C₆ alkyl, O—C₁-C₆ alkyl, or CN. In oneaspect, R⁶ is F, methyl, O-methyl, or CN. In a further aspect, R⁶ is F,O-methyl, or CN. In a further aspect, R⁶ is at the 2- or 4-position. Ina further aspect, at least one R⁶ is F. In a further aspect, R⁶ is2-fluoro or 4-fluoro. In a further aspect, R⁶ is 2-fluoro. In a furtheraspect, R⁶ is 4-fluoro.

In one aspect, A¹ is N. In another aspect, A² is N. In another aspect,A³ is N.

In one aspect, R⁶¹ is H. In another aspect, R⁶¹ is R⁶.

In one aspect, the present application relates to a compound of any ofthe formulae herein, wherein at least one R⁵ is, or as where applicable,R⁵ is, C₁-C₆ alkyl and R³ is C₁-C₆ alkyl. In one aspect, the presentapplication relates to a compound of any of the formulae herein, whereinat least one R⁵ is, or as where applicable, R⁵ is, C₁-C₃ alkyl and R³ isC₁-C₃ alkyl. In one aspect, the present application relates to acompound of any of the formulae herein, wherein at least one R⁵ is, oras where applicable, R⁵ is, methyl and R³ is C₁-C₆ alkyl. In one aspect,the present application relates to a compound of any of the formulaeherein, wherein at least one R⁵ is, or as where applicable, R⁵ is,methyl and R³ is C₁-C₃ alkyl. In one aspect, the present applicationrelates to a compound of any of the formulae herein, wherein at leastone R⁵ is, or as where applicable, R⁵ is, C₁-C₆ alkyl and R³ is methyl.In one aspect, the present application relates to a compound of any ofthe formulae herein, wherein at least one R⁵ is, or as where applicable,R⁵ is, C₁-C₃ alkyl and R³ is methyl. In one aspect, the presentapplication relates to a compound of any of the formulae herein, whereinat least one R⁵ is, or as where applicable, R⁵ is, methyl and R³ ismethyl.

In one aspect, the present application relates to a compound of any ofthe formulae herein, wherein at least one R⁵ is, or as where applicable,R⁵ is, C₁-C₆ alkyl and at least one R⁶ is, or as where applicable, R⁶is, halogen. In one aspect, the present application relates to acompound of any of the formulae herein, wherein at least one R⁵ is, oras where applicable, R⁵ is, C₁-C₃ alkyl and at least one R⁶ is, or aswhere applicable, R⁶ is, halogen. In one aspect, the present applicationrelates to a compound of any of the formulae herein, wherein at leastone R⁵ is, or as where applicable, R⁵ is, methyl and at least one R⁶ is,or as where applicable, R⁶ is, halogen. In one aspect, the presentapplication relates to a compound of any of the formulae herein, whereinat least one R⁵ is, or as where applicable, R⁵ is, C₁-C₆ alkyl and atleast one R⁶ is, or as where applicable, R⁶ is, F. In one aspect, thepresent application relates to a compound of any of the formulae herein,wherein at least one R⁵ is, or as where applicable, R⁵ is, C₁-C₃ alkyland at least one R⁶ is, or as where applicable, R⁶ is, F. In one aspect,the present application relates to a compound of any of the formulaeherein, wherein at least one R⁵ is, or as where applicable, R⁵ is,methyl and at least one R⁶ is, or as where applicable, R⁶ is, F.

In one aspect, the present application relates to a compound of any ofthe formulae herein, wherein R³ is C₁-C₆ alkyl and at least one R⁶ is,or as where applicable, R⁶ is, halogen. In one aspect, the presentapplication relates to a compound of any of the formulae herein, whereinR³ is C₁-C₃ alkyl and at least one R⁶ is, or as where applicable, R⁶ is,halogen. In one aspect, the present application relates to a compound ofany of the formulae herein, wherein R³ is methyl and at least one R⁶ is,or as where applicable, R⁶ is, halogen. In one aspect, the presentapplication relates to a compound of any of the formulae herein, whereinR³ is C₁-C₆ alkyl and at least one R⁶ is, or as where applicable, R⁶ is,F. In one aspect, the present application relates to a compound of anyof the formulae herein, wherein R³ is C₁-C₃ alkyl and at least one R⁶is, or as where applicable, R⁶ is, F. In one aspect, the presentapplication relates to a compound of any of the formulae herein, whereinR³ is methyl and at least one R⁶ is, or as where applicable, R⁶ is, F.

In one aspect, the present application relates to a compound of any ofthe formulae herein, wherein at least one R⁵ is, or as where applicable,R⁵ is, C₁-C₆ alkyl, R³ is C₁-C₆ alkyl, and at least one R⁶ is, or aswhere applicable, R⁶ is, halogen. In one aspect, the present applicationrelates to a compound of any of the formulae herein, wherein at leastone R⁵ is, or as where applicable, R⁵ is, C₁-C₃ alkyl, R³ is C₁-C₃alkyl, and at least one R⁶ is, or as where applicable, R⁶ is, halogen.In one aspect, the present application relates to a compound of any ofthe formulae herein, wherein at least one R⁵ is, or as where applicable,R⁵ is, methyl, R³ is C₁-C₆ alkyl, and at least one R⁶ is, or as whereapplicable, R⁶ is, halogen. In one aspect, the present applicationrelates to a compound of any of the formulae herein, wherein at leastone R⁵ is, or as where applicable, R⁵ is, methyl, R³ is C₁-C₃ alkyl, andat least one R⁶ is, or as where applicable, R⁶ is, halogen. In oneaspect, the present application relates to a compound of any of theformulae herein, wherein at least one R⁵ is, or as where applicable, R⁵is, C₁-C₆ alkyl, R³ is methyl, and at least one R⁶ is, or as whereapplicable, R⁶ is, halogen. In one aspect, the present applicationrelates to a compound of any of the formulae herein, wherein at leastone R⁵ is, or as where applicable, R⁵ is, C₁-C₃ alkyl, R³ is methyl, andat least one R⁶ is, or as where applicable, R⁶ is, halogen. In oneaspect, the present application relates to a compound of any of theformulae herein, wherein at least one R⁵ is, or as where applicable, R⁵is, methyl, R³ is methyl, and at least one R⁶ is, or as whereapplicable, R⁶ is, halogen.

In one aspect, the present application relates to a compound of any ofthe formulae herein, wherein at least one R⁵ is, or as where applicable,R⁵ is, C₁-C₆ alkyl, R³ is C₁-C₆ alkyl, and at least one R⁶ is, or aswhere applicable, R⁶ is, F. In one aspect, the present applicationrelates to a compound of any of the formulae herein, wherein at leastone R⁵ is, or as where applicable, R⁵ is, C₁-C₃ alkyl, R³ is C₁-C₃alkyl, and at least one R⁶ is, or as where applicable, R⁶ is, F. In oneaspect, the present application relates to a compound of any of theformulae herein, wherein at least one R⁵ is, or as where applicable, R⁵is, methyl, R³ is C₁-C₆ alkyl, and at least one R⁶ is, or as whereapplicable, R⁶ is, F. In one aspect, the present application relates toa compound of any of the formulae herein, wherein at least one R⁵ is, oras where applicable, R⁵ is, methyl, R³ is C₁-C₃ alkyl, and at least oneR⁶ is, or as where applicable, R⁶ is, F. In one aspect, the presentapplication relates to a compound of any of the formulae herein, whereinat least one R⁵ is, or as where applicable, R⁵ is, C₁-C₆ alkyl, R³ ismethyl, and at least one R⁶ is, or as where applicable, R⁶ is, F. In oneaspect, the present application relates to a compound of any of theformulae herein, wherein at least one R⁵ is, or as where applicable, R⁵is, C₁-C₃ alkyl, R³ is methyl, and at least one R⁶ is, or as whereapplicable, R⁶ is, F. In one aspect, the present application relates toa compound of any of the formulae herein, wherein at least one R⁵ is, oras where applicable, R⁵ is, methyl, R³ is methyl, and at least one R⁶is, or as where applicable, R⁶ is, F.

Representative compounds of the application are listed in Table 1.

TABLE 1 Compound Melting Point No. Structure (° C.) 100

154-155 101

164-166 102

165-167 103

148-151 104

106-108 105

 98-100 106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

In one aspect, a compound of the application displays high brainpermeability. Brain permeability can be measured by various methodsknown in the art. For example, brain permeability can be measured bycalculating the ratio between the concentration of a compound of theapplication in the brain and the concentration of the compound in theplasma (i.e., B:P ratio). In one aspect, a compound of the applicationhas a B:P ratio of at least 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,1.9, or 2.0 at 1 hour after administration of the compound to a subject.In one aspect, a compound of the application has a B:P ratio of at least1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 at 1 hour after administration of thecompound to a subject. In one aspect, a compound of the application hasa B:P ratio of at least 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, or2.3 at 2 hours after administration of the compound to a subject. In oneaspect, a compound of the application has a B:P ratio of at least 1.9,2.0, 2.1, 2.2, or 2.3 at 2 hours after administration of the compound toa subject. In one aspect, a compound of the application has a B:P ratioof at least 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 at 4 hoursafter administration of the compound to a subject. In one aspect, acompound of the application has a B:P ratio of at least 2.2, 2.3, 2.4,or 2.5 at 4 hours after administration of the compound to a subject. Inone aspect, the compound that displays high brain permeability is acompound of formula (VIIa), (VIIb), (VIIc), (VIId), or (VIIe) wherein R⁶is F. In a further aspect, the compound that displays high brainpermeability is a compound of formula (VIIa), (VIIb), (VIIc), (VIId), or(VIIe), wherein R⁶ is 2-fluoro or 4-fluoro. In a further aspect, thecompound that displays high brain permeability is a compound of formula(VIIa), (VIIb), (VIIc), (VIId), or (VIIe), wherein R⁶ is 2-fluoro. In afurther aspect, the compound that displays high brain permeability is acompound of formula (VIIa), (VIIb), (VIIc), (VIId), or (VIIe), whereinR⁶ is 4-fluoro.

In one aspect, a compound of the application displays a low meltingpoint (M.P.). In one aspect, a low M.P. is below 150° C., 145° C., 140°C., 135° C., 130° C., 125° C., 120° C., 115° C., 110° C., 105° C., 100°C., 95° C., 90° C., or 85° C. In a further aspect, a low M.P. is below115° C., 110° C., 105° C., 100° C., 95° C., 90° C., or 85° C. In oneaspect, the compound that has a low M.P. is any compound of theapplication, wherein R³ is not H. In a further aspect, R³ is C₁-C₆alkyl. In a further aspect, R³ is methyl.

In one aspect, a compound of the application displays improved aqueoussolubility compared to

i.e., Compound Y, a compound known to be useful in treating diseases anddisorders that are modulated by tyrosine kinase inhibition, at a pH of4.4. In one aspect, a compound of the application is about 10 to about100 times more soluble in water at a pH of 4.4 compared to Compound Y.In a further aspect, the compound is about 15 to about 75 times moresoluble in water at a pH of 4.4 compared to Compound Y. In a furtheraspect, the compound is about 20 to about 50 times more soluble in waterat a pH of 4.4 compared to Compound Y. In a further aspect, the compoundis about 20 times more soluble in water at a pH of 4.4 compared toCompound Y. In a further aspect, the compound is about 30 times moresoluble in water at a pH of 4.4 compared to Compound Y. In a furtheraspect, the compound is about 40 times more soluble in water at a pH of4.4 compared to Compound Y. In a further aspect, the compound is about50 times more soluble in water at a pH of 4.4 compared to Compound Y.

In one aspect, a compound of the application has a solubility of about30 μM to about 100 μM in water at a pH of 4.4. In a further aspect, thecompound has a solubility of about 40 to about 90 μM in water at a pH of4.4. In a further aspect, the compound has a solubility of about 40 μMto about 80 μM in water at a pH of 4.4. In a further aspect, thecompound has a solubility of about 40 μM to about 70 μM in water at a pHof 4.4. In a further aspect, the compound has a solubility of about 40μM in water at a pH of 4.4. In a further aspect, the compound has asolubility of about 50 μM in water at a pH of 4.4. In a further aspect,the compound has a solubility of about 60 μM in water at a pH of 4.4. Ina further aspect, the compound has a solubility of about 70 μM in waterat a pH of 4.4. In a further aspect, the compound has a solubility ofabout 80 μM in water at a pH of 4.4. In a further aspect, the compoundhas a solubility of about 90 μM in water at a pH of 4.4.

In one aspect, a compound of the application displays improved aqueoussolubility compared to Compound Y at a pH of 7.4. In one aspect, acompound of the application is about 5 to about 60 times more soluble inwater at a pH of 7.4 compared to Compound Y. In a further aspect, thecompound is about 10 to about 50 times more soluble in water at a pH of7.4 compared to Compound Y. In a further aspect, the compound is about15 to about 40 times more soluble in water at a pH of 7.4 compared toCompound Y. In a further aspect, the compound is about 10 to about 20times more soluble in water at a pH of 7.4 compared to Compound Y. In afurther aspect, the compound is about 20 to about 30 times more solublein water at a pH of 7.4 compared to Compound Y. In a further aspect, thecompound is about 30 to about 40 times more soluble in water at a pH of7.4 compared to Compound Y. In a further aspect, the compound is about40 to about 50 times more soluble in water at a pH of 7.4 compared toCompound Y.

In one aspect, a compound of the application has a solubility of about10 μM to about 40 μM in water at a pH of 7.4. In a further aspect, thecompound has a solubility of about 15 μM to about 30 μM in water at a pHof 7.4. In a further aspect, the compound has a solubility of about 15μM in water at a pH of 7.4. In a further aspect, the compound has asolubility of about 20 μM in water at a pH of 7.4. In a further aspect,the compound has a solubility of about 25 μM. In a further aspect, thecompound has a solubility of about 30 μM in water at a pH of 7.4.

In one aspect, the application relates to a pharmaceutical compositioncomprising a compound of the application, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, and a pharmaceuticallyacceptable carrier.

In one aspect, the application relates to a method of preventing ortreating a disease or disorder comprising administering to a subject inneed thereof an effective amount of a compound of the application, e.g.,a compound according to formula A, I, II, III, IVa, IVb, IVc, IVd, Va,Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc, VIId, or VIIe or apharmaceutically acceptable salt, solvate, or prodrug thereof, or apharmaceutical composition of the application.

In one aspect, the application relates to a method of preventing ortreating a disease or disorder comprising administering to a subject inneed thereof an effective amount of a compound of the application, e.g.,a compound according to formula A, I, II, III, IVa, IVb, IVc, IVd, Va,Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc, VIId, or VIIe or apharmaceutically acceptable salt, solvate, or prodrug thereof, or apharmaceutical composition of the application, wherein R⁵ is in theS-configuration. In one aspect, R⁵ is in the S-configuration and isselected from the group consisting of halogen, OH, CONH₂, COOH, CN, N₃,C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl. In one aspect, R⁵ is inthe S-configuration and is selected from the group consisting ofhalogen, OH, and C₁-C₆ alkyl. In one aspect, R⁵ is in theS-configuration and is halogen. In one aspect, R⁵ is in theS-configuration and is OH. In one aspect, R⁵ is in the S-configurationand is C₁-C₆ alkyl. In one aspect, R⁵ is in the S-configuration and ismethyl.

In one aspect, the application relates to the use of a compound of theapplication, e.g., a compound according to formula A, I, II, III, IVa,IVb, IVc, IVd, Va, Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc,VIId, or VIIe or a pharmaceutically acceptable salt, solvate, or prodrugthereof, or a pharmaceutical composition of the application, forpreventing or treating a disease or disorder in a subject in needthereof.

In one aspect, the application relates to the use of a compound of theapplication, e.g., a compound according to formula A, I, II, III, IVa,IVb, IVc, IVd, Va, Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc,VIId, or VIIe or a pharmaceutically acceptable salt, solvate, or prodrugthereof, or a pharmaceutical composition of the application, forpreventing or treating a disease or disorder in a subject in needthereof, wherein R⁵ is in the S-configuration. In one aspect, R⁵ is inthe S-configuration and is selected from the group consisting ofhalogen, OH, CONH₂, COOH, CN, N₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆alkynyl. In one aspect, R⁵ is in the S-configuration and is selectedfrom the group consisting of halogen, OH, and C₁-C₆ alkyl. In oneaspect, R⁵ is in the S-configuration and is halogen. In one aspect, R⁵is in the S-configuration and is OH. In one aspect, R⁵ is in theS-configuration and is C₁-C₆ alkyl. In one aspect, R⁵ is in theS-configuration and is methyl.

In one aspect, the application relates to the use of a compound of theapplication, e.g., a compound according to formula A, I, II, III, IVa,IVb, IVc, IVd, Va, Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc,VIId, or VIIe or a pharmaceutically acceptable salt, solvate, or prodrugthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for preventing or treating a disease ordisorder in a subject in need thereof.

In one aspect, the application relates to the use of a compound of theapplication, e.g., a compound according to formula A, I, II, III, IVa,IVb, IVc, IVd, Va, Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc,VIId, or VIIe or a pharmaceutically acceptable salt, solvate, or prodrugthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for preventing or treating a disease ordisorder in a subject in need thereof, wherein R⁵ is in theS-configuration. In one aspect, R⁵ is in the S-configuration and isselected from the group consisting of halogen, OH, CONH₂, COOH, CN, N₃,C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl. In one aspect, R⁵ is inthe S-configuration and is selected from the group consisting ofhalogen, OH, and C₁-C₆ alkyl. In one aspect, R⁵ is in theS-configuration and is halogen. In one aspect, R⁵ is in theS-configuration and is OH. In one aspect, R⁵ is in the S-configurationand is C₁-C₆ alkyl. In one aspect, R⁵ is in the S-configuration and ismethyl.

In one aspect, the application relates to a compound of the application,e.g., a compound according to formula A, I, II, III, IVa, IVb, IVc, IVd,Va, Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc, VIId, or VIIe or apharmaceutically acceptable salt, solvate, or prodrug thereof, or apharmaceutical composition of the application for use in preventing ortreating a disease or disorder in a subject in need thereof.

In one aspect, the application relates to a compound of the application,e.g., a compound according to formula A, I, II, III, IVa, IVb, IVc, IVd,Va, Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc, VIId, or VIIe or apharmaceutically acceptable salt, solvate, or prodrug thereof, or apharmaceutical composition of the application, for use in preventing ortreating a disease or disorder in a subject in need thereof, wherein R⁵is in the S-configuration. In one aspect, R⁵ is in the S-configurationand is selected from the group consisting of halogen, OH, CONH₂, COOH,CN, N₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl. In one aspect, R⁵is in the S-configuration and is selected from the group consisting ofhalogen, OH, and C₁-C₆ alkyl. In one aspect, R⁵ is in theS-configuration and is halogen. In one aspect, R⁵ is in theS-configuration and is OH. In one aspect, R⁵ is in the S-configurationand is C₁-C₆ alkyl. In one aspect, R⁵ is in the S-configuration and ismethyl.

One aspect of this application provides compounds that are useful forthe treatment of diseases, disorders, and conditions characterized byexcessive or abnormal cell proliferation. Such diseases include, but arenot limited to, a proliferative or hyperproliferative disease. Examplesof proliferative and hyperproliferative diseases include, withoutlimitation, cancer.

In one aspect, the disorder is proliferative disorder. In anotheraspect, the proliferative disorder is selected from a group consistingof a proliferative disorder of the skin, such as psoriasis and actinickeratosis. In another aspect, the proliferative disorder is selectedfrom a group consisting of brain cancer, liver cancer, pancreaticcancer, gastric cancer, breast cancer, ovarian cancer, nerve cancer,bone cancer, cervical cancer, colorectal cancer, esophageal cancer,kidney cancer, lung cancer, muscle cancer, pharyngeal cancer, placentalcancer, prostate cancer, skin cancer, soft tissue cancer, stomachcancer, thyroid cancer, tongue cancer, uterine cancer, bladder cancer,blood cancer, hematologic tumor, childhood leukemia, lymphoma, multiplemyeloma, Hodgkin's disease, lymphoma of lymphocytic origin, lymphoma ofcutaneous origin, acute leukemia, chronic leukemia, acute lymphoblasticleukemia, plasma cell neoplasm, lymphoid neoplasm, cancer associatedwith AIDS, acute myelocytic leukemia, chronic myelocytic leukemia,malignant melanoma, non-melanoma skin cancer, epidermic cyst, dermoidcyst, lipoma, adenoma, capillary or cutaneous hemangioma, lymphangioma,nevi lesion, teratoma, nephroma, myofibromatosis, osteoplastic tumor,dysplastic mass, and dysplasia.

In one aspect, the disorder is cancer. In another aspect, the cancer isselected from a group consisting of bladder cancer, blood cancer, bonecancer, brain cancer, nerve cancer, breast cancer, cervical cancer,colorectal cancer, esophageal cancer, kidney cancer, lung cancer, musclecancer, ovarian cancer, pancreatic cancer, pharyngeal cancer, placentalcancer, prostate cancer, skin cancer, soft tissue cancer, stomachcancer, gastric cancer, thyroid cancer, tongue cancer, and uterinecancer. In another aspect, the cancer is brain cancer. In a furtheraspect, the brain cancer is glioblastoma.

In one aspect, the application relates to a method of preventing ortreating a brain cancer comprising administering to a subject in needthereof an effective amount of a compound of the application, e.g., acompound according to formula A, I, II, III, IVa, IVb, IVc, IVd, Va, Vb,Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc, VIId, or VIIe or apharmaceutically acceptable salt, solvate, or prodrug thereof, or apharmaceutical composition of the application. In one aspect, R⁵ is inthe S-configuration. In one aspect, R⁵ is in the S-configuration and isselected from the group consisting of halogen, OH, CONH₂, COOH, CN, N₃,C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl. In one aspect, R⁵ is inthe S-configuration and is selected from the group consisting ofhalogen, OH, and C₁-C₆ alkyl. In one aspect, R⁵ is in theS-configuration and is halogen. In one aspect, R⁵ is in theS-configuration and is OH. In one aspect, R⁵ is in the S-configurationand is C₁-C₆ alkyl. In one aspect, R⁵ is in the S-configuration and ismethyl.

In one aspect, the application relates to the use of a compound of theapplication, e.g., a compound according to formula A, I, II, III, IVa,IVb, IVc, IVd, Va, Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc,VIId, or VIIe or a pharmaceutically acceptable salt, solvate, or prodrugthereof, or a pharmaceutical composition of the application, forpreventing or treating a brain cancer. In one aspect, R⁵ is in theS-configuration. In one aspect, R⁵ is in the S-configuration and isselected from the group consisting of halogen, OH, CONH₂, COOH, CN, N₃,C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl. In one aspect, R⁵ is inthe S-configuration and is selected from the group consisting ofhalogen, OH, and C₁-C₆ alkyl. In one aspect, R⁵ is in theS-configuration and is halogen. In one aspect, R⁵ is in theS-configuration and is OH. In one aspect, R⁵ is in the S-configurationand is C₁-C₆ alkyl. In one aspect, R⁵ is in the S-configuration and ismethyl.

In one aspect, the application relates to the use of a compound of theapplication, e.g., a compound according to formula A, I, II, III, IVa,IVb, IVc, IVd, Va, Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc,VIId, or VIIe or a pharmaceutically acceptable salt, solvate, or prodrugthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for preventing or treating a brain cancer.In one aspect, R⁵ is in the S-configuration. In one aspect, R⁵ is in theS-configuration and is selected from the group consisting of halogen,OH, CONH₂, COOH, CN, N₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl.In one aspect, R⁵ is in the S-configuration and is selected from thegroup consisting of halogen, OH, and C₁-C₆ alkyl. In one aspect, R⁵ isin the S-configuration and is halogen. In one aspect, R⁵ is in theS-configuration and is OH. In one aspect, R⁵ is in the S-configurationand is C₁-C₆ alkyl. In one aspect, R⁵ is in the S-configuration and ismethyl.

In one aspect, the application relates to a compound of the application,e.g., a compound according to formula A, I, II, III, IVa, IVb, IVc, IVd,Va, Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb, VIIc, VIId, or VIIe or apharmaceutically acceptable salt, solvate, or prodrug thereof, or apharmaceutical composition of the application, for use in preventing ortreating a brain cancer. In one aspect, R⁵ is in the S-configuration. Inone aspect, R⁵ is in the S-configuration and is selected from the groupconsisting of halogen, OH, CONH₂, COOH, CN, N₃, C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl. In one aspect, R⁵ is in the S-configurationand is selected from the group consisting of halogen, OH, and C₁-C₆alkyl. In one aspect, R⁵ is in the S-configuration and is halogen. Inone aspect, R⁵ is in the S-configuration and is OH. In one aspect, R⁵ isin the S-configuration and is C₁-C₆ alkyl. In one aspect, R⁵ is in theS-configuration and is methyl.

In one aspect, the proliferative disorder is brain cancer. In anotheraspect, the brain cancer is a primary tumor. In another aspect, theprimary brain tumor is selected from glioblastoma, astrocytoma,meningioma, pituitary adenoma, vestibular schwannoma, ependymoma,oligodendroglioma, choroid plexus papillomas, and medullablastoma.

In one aspect, the disorder is angiogenic disorder. In another aspect,the angiogenic disorder is selected from cancer, wet maculardegeneration, and dry macular degeneration.

In one aspect, the disorder is abnormal vascularization.

In one aspect, the disorder is ocular myopathy.

In one aspect, the compound of the application or composition isadministered orally, parenterally, subcutaneously, intravenously,intramuscularly, intraperitoneally, by intranasal instillation, byintracavitary or intravesical instillation, topically, intraarterially,intralesionally, by metering pump, or by application to mucousmembranes. In another aspect, the compound of the application orcomposition is administered orally, parenterally, or intravenously. Inone aspect, the compound of the application or composition isadministered orally.

Definitions

For convenience, certain terms used in the specification, examples andappended claims are collected here.

Protein kinases are a large class of enzymes which catalyze the transferof the γ-phosphate from ATP to the hydroxyl group on the side chain ofSer/Thr or Tyr in proteins and peptides and are intimately involved inthe control of various important cell functions, perhaps most notably:signal transduction, differentiation, and proliferation. There areestimated to be about 2,000 distinct protein kinases in the human body,and although each of these phosphorylates particular protein/peptidesubstrates, they all bind the same second substrate ATP in a highlyconserved pocket. About 50% of the known oncogene products are proteintyrosine kinases (PTKs), and their kinase activity has been shown tolead to cell transformation.

The PTKs can be classified into two categories, the membrane receptorPTKs (e.g., growth factor receptor PTKs) and the non-receptor PTKs(e.g., the Src family of proto-oncogene products and focal adhesionkinase (FAK)). The hyperactivation of Src has been reported in a numberof human cancers, including those of the colon, breast, lung, bladder,and skin, as well as in gastric cancer, hairy cell leukemia, andneuroblastoma.

The phrase “inhibits one or more components of a protein kinasesignaling cascade” means that one or more components of the kinasesignaling cascade are effected such that the function of the cellchanges. Components of a protein kinase signaling cascade include anyproteins involved directly or indirectly in the kinase signaling pathwayincluding second messengers and upstream and downstream targets.

“Treating”, includes any effect, e.g., lessening, reducing, modulating,or eliminating, that results in the improvement of the condition,disease, disorder, etc. “Treating” or “treatment” of a disease stateincludes: (1) inhibiting the disease state, i.e., arresting thedevelopment of the disease state or its clinical symptoms; or (2)relieving the disease state, i.e., causing temporary or permanentregression of the disease state or its clinical symptoms.

“Preventing”, refers to causing the clinical symptoms of the diseasestate not to develop in a subject that may be exposed to or predisposedto the disease state, but does not yet experience or display symptoms ofthe disease state.

As used herein, the term “proliferative disorder” refers to conditionsin which the unregulated and/or abnormal growth of cells can lead to thedevelopment of an unwanted condition or disease, which can be cancerousor non-cancerous, for example a psoriatic condition.

As used herein, the terms “psoriatic condition” or “psoriasis” refers todisorders involving keratinocyte hyperproliferation, inflammatory cellinfiltration, and cytokine alteration.

Exemplary cell proliferative disorder include, but are not limited to,neoplasms, benign tumors, malignant tumors, pre-cancerous conditions, insitu tumors, encapsulated tumors, metastatic tumors, liquid tumors,solid tumors, immunological tumors, hematological tumors, cancers,carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells.

The term “rapidly dividing cell” as used herein is defined as any cellthat divides at a rate that exceeds or is greater than what is expectedor observed among neighboring or juxtaposed cells within the sametissue. A cell proliferative disorder includes a precancer or aprecancerous condition. A cell proliferative disorder includes cancer.

As used herein, the term “cancer” includes solid tumors, such as lung,breast, colon, ovarian, brain, liver, pancreas, prostate, malignantmelanoma, non-melanoma skin cancers, as well as hematologic tumorsand/or malignancies, such as childhood leukemia and lymphomas, multiplemyeloma, Hodgkin's disease, lymphomas of lymphocytic and cutaneousorigin, acute and chronic leukemia such as acute lymphoblastic, acutemyelocytic or chronic myelocytic leukemia, plasma cell neoplasm,lymphoid neoplasm and cancers associated with AIDS. Cancer is a group ofdiseases that may cause almost any sign or symptom. The signs andsymptoms will depend on where the cancer is, the size of the cancer, andhow much it affects the nearby organs or structures. If a cancer spreads(metastasizes), then symptoms may appear in different parts of the body.Cancers include metastatic cancer, for example, cancer that has spreadfrom the place where it first started to another place in the body.

Exemplary cancers include, but are not limited to, adrenocorticalcarcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer,anorectal cancer, cancer of the anal canal, appendix cancer, childhoodcerebellar astrocytoma, childhood cerebral astrocytoma, basal cellcarcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bileduct cancer, intrahepatic bile duct cancer, bladder cancer, urinarybladder cancer, bone and joint cancer, osteosarcoma and malignantfibrous histiocytoma, brain cancer, brain tumor, brain stem glioma,cerebellar astrocytoma, cerebral astrocytoma/malignant glioma,ependymoma, medulloblastoma, supratentorial primitive neuroectodermaltumors, visual pathway and hypothalamic glioma, breast cancer, bronchialadenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous systemcancer, nervous system lymphoma, central nervous system cancer, centralnervous system lymphoma, cervical cancer, childhood cancers, chroniclymphocytic leukemia, chronic myelogenous leukemia, chronicmyeloproliferative disorders, colon cancer, colorectal cancer, cutaneousT-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Seziary Syndrome,endometrial cancer, esophageal cancer, extracranial germ cell tumor,extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer,intraocular melanoma, retinoblastoma, gallbladder cancer, gastric(stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor (GIST), germ cell tumor, ovarian germ cell tumor,gestational trophoblastic tumor glioma, head and neck cancer,hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, ocular cancer, islet cell tumors (endocrinepancreas), Kaposi Sarcoma, kidney cancer, renal cancer, kidney cancer,laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, lip and oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell lung cancer, AIDS-relatedlymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma,Waldenstram macroglobulinemia, medulloblastoma, melanoma, intraocular(eye) melanoma, merkel cell carcinoma, mesothelioma malignant,mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer ofthe tongue, multiple endocrine neoplasia syndrome, mycosis fungoides,myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases,chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma,chronic myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer,ovarian cancer, ovarian epithelial cancer, ovarian low malignantpotential tumor, pancreatic cancer, islet cell pancreatic cancer,paranasal sinus and nasal cavity cancer, parathyroid cancer, penilecancer, pharyngeal cancer, pheochromocytoma, pineoblastoma andsupratentorial primitive neuroectodermal tumors, pituitary tumor, plasmacell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostatecancer, rectal cancer, renal pelvis and ureter, transitional cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, ewingfamily of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterinecancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer(melanoma), merkel cell skin carcinoma, small intestine cancer, softtissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, testicular cancer,throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer,transitional cell cancer of the renal pelvis and ureter and otherurinary organs, gestational trophoblastic tumor, urethral cancer,endometrial uterine cancer, uterine sarcoma, uterine corpus cancer,vaginal cancer, vulvar cancer, and Wilm's Tumor.

The term “brain cancer” encompasses a variety of cancers. There can beactual brain tumors which arise from the brain itself, known as primarybrain cancers of which there are several. The term “brain cancer” refersto malignant tumors i.e., tumors that grow and spread aggressively,overpowering healthy cells by taking up their space, blood, andnutrients. Tumors that do not spread aggressively are called benigntumors. Benign tumors are generally less serious than a malignant tumor,but a benign tumor can still cause problems in the brain. There can alsobe brain metastases, which represent the spread of other cancers, suchas lung or breast to the brain.

Brain tumors are classified by both the cell of the brain that makesthem up and how the tumor looks under the microscope. Primary braintumors arise from any of the cells in the brain, or from specificstructures in the brain. Glia cells support the neurons of the brain andtumors which arise from these cells are known as glial tumors. Themembrane that surrounds the brain can also develop tumors and these areknown as meningiomas. There are other types of tumors, which involveother structures of the brain including ependymoma. The most commonprimary brain tumors are gliomas, meningiomas, pituitary adenomas,vestibular schwannomas, and primitive neuroectodermal tumors(medullablastomas).

Glioblastoma is a malignant rapidly growing astrocytoma of the centralnervous system and usually of a cerebral hemisphere. Synonyms forglioblastoma include glioblastoma multiforme (GBM), giant cellglioblastoma, and multiforme spongioblastoma multiforme. Glioblastoma isthe most common malignant primary brain tumor and has proven verydifficult to treat. These tumors are often aggressive and infiltratesurrounding brain tissue. Glioblastomas arise from glial cells, whichare cells that form the tissue that surrounds and protects other nervecells found within the brain and spinal cord. Glioblastomas are mainlycomposed of star-shaped glial cells known as astrocytes.

The term “glioma” includes any type of brain tumor such as astrocytomas,oligodendrogliomas, ependymomas, and choroid plexus papillomas.Astrocytomas come in four grades based on how fast the cells arereproducing and the likelihood that they will infiltrate nearby tissue.Grades I or II astrocytomas are nonmalignant and may be referred to aslow-grade. Grades III and IV astrocytomas are malignant and may bereferred to as high-grade astrocytomas. Grade II astrocytomas are knownas anaplastic astrocytomas. Grade IV astrocytomas are known asglioblastoma multiforme.

Medulloblastoma is a highly malignant primary brain tumor thatoriginates in the cerebellum or posterior fossa. Originally consideredto be a glioma, medulloblastoma is now known to be of the family ofcranial primitive neuroectodermal tumors (PNET).

Tumors that originate in the cerebellum are referred to asinfratentorial because they occur below the tentorium, a thick membranethat separates the cerebral hemispheres of the brain from thecerebellum. Another term for medulloblastoma is infratentorial PNET.Medulloblastoma is the most common PNET originating in the brain. AllPNET tumors of the brain are invasive and rapidly growing tumors that,unlike most brain tumors, spread through the cerebrospinal fluid (CSF)and frequently metastasize to different locations in the brain andspine. The peak of occurrence of medullablastoma is seven years of age.Seventy percent of medulloblastomas occur in individuals younger than16. Desmoplastic medulloblastoma is encountered especially in adulthood.This type of tumor rarely occurs beyond the fifth decade of life.

Neuroblastoma is a cancer that forms in nerve tissue. The cells ofneuroblastoma usually resemble very primitive developing nerve cellsfound in an embryo or fetus. The term neuro indicates “nerves,” whileblastoma refers to a cancer that affects immature or developing cells.Neurons (nerve cells) are the main component of the brain and spinalcord and of the nerves that connect them to the rest of the body.Neuroblastoma usually begins in the adrenal glands, but it may alsobegin in the spinal cord. Neuroblastoma is the most common extracranialsolid cancer in childhood. In 2007, neuroblastoma was the most commoncancer in infancy, with an annual incidence of about 650 new cases peryear in the US. Close to 50 percent of neuroblastoma cases occur inchildren younger than two years old. It is a neuroendocrine tumor,arising from any neural crest element of the sympathetic nervous systemor SNS. A branch of the autonomic nervous system, the SNS is a nervenetwork that carries messages from the brain throughout the body and isresponsible for the fight-or-flight response and production ofadrenaline or epinephrine.

Neuroepithelioma is malignant tumors of the neuroepithelium.Neuroepithelioma is found most commonly in children and young adults. Itarises most often in the chest wall, pelvis, or extremity, either inbone or soft tissue. Procedures used in the diagnosis may include bloodand urine tests, X rays of the affected bone and the whole body andlungs, bone marrow aspirations, CT scans, and fluoroscopy. Treatmentsinclude surgery, radiation therapy and chemotherapy. Ewing's tumors arean example of a type of peripheral neuroepithelioma.

In addition to psoriatic conditions, the types of proliferative diseaseswhich may be treated using the compositions of the present applicationare epidermic and dermoid cysts, lipomas, adenomas, capillary andcutaneous hemangiomas, lymphangiomas, nevi lesions, teratomas,nephromas, myofibromatosis, osteoplastic tumors, and other dysplasticmasses and the like. The proliferative diseases can include dysplasiasand disorders of the like.

The term “angiogenic disorder” refers to conditions in which theunregulated and/or abnormal growth of blood vessels can lead todevelopment of unwanted condition or disease, which can be cancerous ornon-cancerous, for example, wet and dry macular degeneration.

An “effective amount” of a compound of the disclosed application is thequantity which, when administered to a subject having a disease ordisorder, results in regression of the disease or disorder in thesubject. Thus, an effective amount of a compound of the disclosedapplication is the quantity which, when administered to a subject havinga cell proliferation disorder, results in regression of cell growth inthe subject. The amount of the disclosed compound to be administered toa subject will depend on the particular disorder, the mode ofadministration, co-administered compounds, if any, and thecharacteristics of the subject, such as general health, other diseases,age, sex, genotype, body weight and tolerance to drugs. The skilledartisan will be able to determine appropriate dosages depending on theseand other factors.

As used herein, the term “effective amount” refers to an amount of acompound, or a combination of compounds, of the present applicationeffective when administered alone or in combination as ananti-proliferative agent. For example, an effective amount refers to anamount of the compound present in a formulation or on a medical devicegiven to a recipient patient or subject sufficient to elicit biologicalactivity, for example, anti-proliferative activity, such as e.g.,anti-cancer activity or anti-neoplastic activity. The combination ofcompounds optionally is a synergistic combination. Synergy, asdescribed, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22,pp. 27-55 (1984), occurs when the effect of the compounds whenadministered in combination is greater than the additive effect of thecompounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at sub-optimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, or increased anti-proliferative effect, or some otherbeneficial effect of the combination compared with the individualcomponents.

The term “compounds of the application” or “a compound of theapplication” refers to a compound according to formula A, I, II, III,IVa, IVb, IVc, IVd, Va, Vb, Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb,VIIc, VIId, or VIIe or any specific compound described herein (e.g., acompound in Table 1).

Compound X is of the following structure:

Compound Y is of the following structure:

With respect to the chemical compounds useful in the presentapplication, the following terms can be applicable:

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. Ringdouble bonds, as used herein, are double bonds that are formed betweentwo adjacent ring atoms (e.g., C═C, C═N, or N═N).

The present application is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium, and isotopes of carbon include C-13 and C-14.

The compounds described herein may have asymmetric centers. Compounds ofthe present application containing an asymmetrically substituted atommay be isolated in optically active or racemic forms. It is well knownin the art how to prepare optically active forms, such as by resolutionof racemic forms or by synthesis from optically active startingmaterials. Many geometric isomers of olefins, C═N double bonds, and thelike can also be present in the compounds described herein, and all suchstable isomers are contemplated in the present application. Cis andtrans geometric isomers of the compounds of the present application aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic, and geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomeric form is specifically indicated. Alltautomers of shown or described compounds are also considered to be partof the present application.

When any variable (e.g., R₅) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R₅ moieties,then the group may optionally be substituted with up to two R₅ moietiesand R₅ at each occurrence is selected independently from the definitionof R₅. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

Compounds of the present application that contain nitrogens can beconverted to N-oxides by treatment with an oxidizing agent (e.g.,3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxides) to affordother compounds of the present application. Thus, all shown and claimednitrogen-containing compounds are considered, when allowed by valencyand structure, to include both the compound as shown and its N-oxidederivative (which can be designated as N→O or N⁺—O⁻). Furthermore, inother instances, the nitrogens in the compounds of the presentapplication can be converted to N-hydroxy or N-alkoxy compounds. Forexample, N-hydroxy compounds can be prepared by oxidation of the parentamine by an oxidizing agent such as m-CPBA. All shown and claimednitrogen-containing compounds are also considered, when allowed byvalency and structure, to cover both the compound as shown and itsN-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R issubstituted or unsubstituted C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl,C₃₋₁₄ carbocycle, or 3-14-membered heterocycle) derivatives.

When an atom or chemical moiety is followed by a subscripted numericrange (e.g., C₁₋₆), the application is meant to encompass each numberwithin the range as well as all intermediate ranges. For example, “C₁₋₆alkyl” is meant to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5,1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6carbons.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁₋₆ alkyl is intended toinclude C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl. “Alkyl”further includes alkyl groups that have oxygen, nitrogen, sulfur orphosphorous atoms replacing one or more hydrocarbon backbone carbonatoms. In certain embodiments, a straight chain or branched chain alkylhas six or fewer carbon atoms in its backbone (e.g., C₁-C₆ for straightchain, C₃-C₆ for branched chain), and in another embodiment, a straightchain or branched chain alkyl has four or fewer carbon atoms.

“Substituted alkyl” refers to alkyl moieties having substituentsreplacing one or more hydrogen on one or more carbons of the hydrocarbonbackbone. Such substituents can include, for example, alkyl, alkenyl,alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Cycloalkyl” refers to cyclic moieties having 3 to 14 carbon atoms intheir ring structure. In another embodiment, cycloalkyls have 3 to 8carbon atoms in their ring structure. In another embodiment, cycloalkylshave 5 or 6 carbons in the ring structure. Cycloalkyls can be furthersubstituted, e.g., with the substituents described above.

“Alkenyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double bond. For example, the term “alkenyl” includesstraight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chainalkenyl groups, alkyl or alkenyl substituted cycloalkenyl groups, andcycloalkyl or cycloalkenyl substituted alkenyl groups. The term“alkenyl” further includes alkenyl groups, which include oxygen,nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbonbackbone carbons. In certain embodiments, a straight chain or branchedchain alkenyl group has six or fewer carbon atoms in its backbone (e.g.,C₂-C₆ for straight chain, C₃-C₆ for branched chain). The term “C₂-C₆”includes alkenyl groups containing two to six carbon atoms. The term“C₃-C₆” includes alkenyl groups containing three to six carbon atoms.

“Substituted alkenyl” refers to alkenyl moieties having substituentsreplacing one or more hydrogen on one or more hydrocarbon backbonecarbon atoms. Such substituents can include, for example, alkyl groups,alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Cycloalkenyl,” e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, refers to cyclic moieties having 3 to 14carbon atoms in their ring structure and at least one double bond. Inanother emodiment cycloalkenyls may have from 3 to 8 carbon atoms intheir ring structure. In another emodiment cycloalkenyl groups may have5 or 6 carbons in the ring structure. Cycloalkenyls can be furthersubstituted, e.g., with the substituents described above.

“Alkynyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but which containat least one triple bond. For example, “alkynyl” includes straight-chainalkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octynyl, nonynyl, decynyl), branched-chain alkynyl groups, andcycloalkyl or cycloalkenyl substituted alkynyl groups. The term“alkynyl” further includes alkynyl groups having oxygen, nitrogen,sulfur or phosphorous atoms replacing one or more hydrocarbon backbonecarbons. In certain embodiments, a straight chain or branched chainalkynyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₄-C₆ for branched chain). The term “C₂-C₆” includesalkynyl groups containing two to six carbon atoms. The term “C₃-C₆”includes alkynyl groups containing three to six carbon atoms.

“Substituted alkynyl” refers to alkynyl moieties having substituentsreplacing a hydrogen on one or more hydrocarbon backbone carbon atoms.Such substituents can include, for example, alkyl groups, alkynylgroups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Cycloalkynyl,” e.g., cyclooctynyl, refers to cyclic moieties having 8to 14 carbon atoms in their ring structure and at least one triple bond.In one emodiment the cycloalkynyl moiety may have 8 or 9 carbons in thering structure. Cycloalkynyls can be further substituted, e.g., with thesubstituents described above.

Unless the number of carbons is otherwise specified, “lower alkyl”includes an alkyl group, as defined above, but having from one to ten,or in another embodiment from one to six, carbon atoms in its backbonestructure. “Lower alkenyl” and “lower alkynyl” have chain lengths of,for example, 2-6 carbon atoms.

An “alkylaryl” or an “aralkyl” moiety is an alkyl substituted with anaryl (e.g., phenylmethyl (benzyl)).

“Aryl” includes groups with aromaticity, including 5- and 6-membered“unconjugated”, or single-ring, aromatic groups that may include fromzero to four heteroatoms, as well as “conjugated”, or multicyclic,systems with at least one aromatic ring. Examples of aryl groups includebenzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole,imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine,pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, theterm “aryl” includes multicyclic aryl groups, e.g., tricyclic, bicyclic,e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole,benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline,isoquinoline, napthridine, indole, benzofuran, purine, benzofuran,deazapurine, or indolizine. Those aryl groups having heteroatoms in thering structure may also be referred to as “aryl heterocycles”,“heterocycles,” “heteroaryls” or “heteroaromatics”. The aromatic ringcan be substituted at one or more ring positions with such substituentsas described above, as for example, halogen, hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino(including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Arylgroups can also be fused or bridged with alicyclic or heterocyclicrings, which are not aromatic so as to form a multicyclic system (e.g.,tetralin, methylenedioxyphenyl).

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo. The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

The term “haloalkyl” refers to both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen (for example—C_(v)F_(w) wherein v=1 to 3 and w=1 to (2v+1)). Examples of haloalkylinclude, but are not limited to, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl.

The term “non-hydrogen substituent” refers to substituents other thanhydrogen. Nonlimiting examples include alkyl groups, alkoxy groups,halogen groups, hydroxyl groups, aryl groups, etc.

As used herein, “carbocycle” or “carbocyclic ring” is intended to meanany stable monocyclic, bicyclic, or tricyclic ring having the specifiednumber of carbons, any of which may be saturated, unsaturated, oraromatic. For example a C₃₋₁₄ carbocycle is intended to mean a mono-,bi-, or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14carbon atoms.

Examples of carbocycles include, but are not limited to, cyclopropyl,cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl,cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl,cyclooctenyl, cyclooctynyl, cyclooctadienyl, fluorenyl, phenyl,naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. Bridged rings arealso included in the definition of carbocycle, including, for example,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, and[2.2.2]bicyclooctane. A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. In one embodiment, bridgerings are one or two carbon atoms. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge. Fused (e.g., naphthyl and tetrahydronaphthyl) and spirorings are also included.

As used herein, the term “heterocycle” or “heterocyclic” is intended tomean any stable monocyclic, bicyclic, or tricyclic ring which issaturated, unsaturated, or aromatic and comprises carbon atoms and oneor more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from the group consisting ofnitrogen, oxygen, and sulfur. A bicyclic or tricyclic heterocycle mayhave one or more heteroatoms located in one ring, or the heteroatoms maybe located in more than one ring. The nitrogen and sulfur heteroatomsmay optionally be oxidized (i.e., N→O and S(O)_(p), where p=1 or 2).When a nitrogen atom is included in the ring it is either N or NH,depending on whether or not the nitrogen atom is attached to a doublebond in the ring (i.e., a hydrogen is present if needed to maintain thetri-valency of the nitrogen atom). The nitrogen atom may be substitutedor unsubstituted (i.e., N or NR wherein R is H or another substituent,as defined). The heterocyclic ring may be attached to its pendant groupat any heteroatom or carbon atom that results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized. In one embodiment, when thetotal number of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. Bridged rings are alsoincluded in the definition of heterocycle. A bridged ring occurs whenone or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon ornitrogen atoms. Bridges include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.Spiro and fused rings are also included.

As used herein, the term “aromatic heterocycle” or “heteroaryl” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclicaromatic heterocyclic ring or 7, 8, 9, 10, 11, or 12-membered bicyclicaromatic heterocyclic ring which consists of carbon atoms and one ormore heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In the case of bicyclic heterocyclicaromatic rings, only one of the two rings needs to be aromatic (e.g.,2,3-dihydroindole), though both may be (e.g., quinoline). The secondring can also be fused or bridged as defined above for heterocycles. Thenitrogen atom may be substituted or unsubstituted (i.e., N or NR whereinR is H or another substituent, as defined). The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), wherep=1 or 2). It is to be noted that total number of S and O atoms in thearomatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

“Polycyclyl” or “polycyclic radical” refers to two or more cyclic rings(e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocyclyls) in which two or more carbons are common to two adjoiningrings. Rings that are joined through non-adjacent atoms are termed“bridged” rings. Each of the rings of the polycycle can be substitutedwith such substituents as described above, as for example, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkylamino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or anaromatic or heteroaromatic moiety.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent application includes all isomers such as geometrical isomer,optical isomer based on an asymmetrical carbon, stereoisomer, tautomerand the like which occur structurally and an isomer mixture and is notlimited to the description of the formula for convenience, and may beany one of isomer or a mixture. Therefore, an asymmetrical carbon atommay be present in the molecule and an optically active compound and aracemic compound may be present in the present compound, but the presentapplication is not limited to them and includes any one. In addition, acrystal polymorphism may be present but is not limiting, but any crystalform may be single or a crystal form mixture, or an anhydride orhydrate. Further, so-called metabolite which is produced by degradationof the present compound in vivo is included in the scope of the presentapplication.

“Isomerism” means compounds that have identical molecular formulae butthat differ in the nature or the sequence of bonding of their atoms orin the arrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

“Chiral isomer” means a compound with at least one chiral center. It hastwo enantiomeric forms of opposite chirality and may exist either as anindividual enantiomer or as a mixture of enantiomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”. A compound that has more thanone chiral center has 2^(n-1) enantiomeric pairs, where n is the numberof chiral centers. Compounds with more than one chiral center may existas either an individual diastereomer or as a mixture of diastereomers,termed a “diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al, Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn etal., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J., Chem.Educ. 1964, 41, 116).

“Enantiomerically pure” or “enantiopure” refers to a sample of a chiralsubstance all of whose molecules (within the limits of detection) havethe same chirality sense. In one aspect, a compound of the applicationis in an enantiopure form, such as in about 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 97%, 97%, 98%, 99%, or greater than 99%enantiomeric excess. In another aspect, the enantiomeric excess is about90%, 95%, 97%, 99%, or greater than 99%. In another aspect, theenantiomeric excess is about 95%, 97%, 99%, or greater than 99%. Inanother aspect, the enantiomeric excess is about 99% or greater than99%. In another aspect, In another aspect, the enantiomeric excess isabout greater than 99%.

“Enantiomeric excess” or “ee” refers to a measure for how much of oneenantiomer is present compared to the other. For a mixture of R and Senantiomers, the percent enantiomeric excess is defined as |R-S|*100,where R and S are the respective mole or weight fractions of enantiomersin a mixture such that R+S=1. With knowledge of the optical rotation ofa chiral substance, the percent enantiomeric excess is defined as([α]_(obs)/[α]_(max))*100, where [α]_(obs) is the optical rotation ofthe mixture of enantiomers and [α]_(max) is the optical rotation of thepure enantiomer. Determination of enantiomeric excess is possible usinga variety of analytical techniques, including NMR spectroscopy, chiralcolumn chromatography or optical polarimetry.

“Geometric Isomers” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Further, the structures and other compounds discussed in thisapplication include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques, ithas been possible to separate mixtures of two atropic isomers in selectcases.

Additionally, the compounds of the present application, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules. Nonlimitingexamples of hydrates include monohydrates, dihydrates, etc. Nonlimitingexamples of solvates include ethanol solvates, acetone solvates, etc.

“Solvates” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Tautomers” refers to compounds whose structures differ markedly inarrangement of atoms, but which exist in easy and rapid equilibrium. Itis to be understood that the compounds of the application may bedepicted as different tautomers. It should also be understood that whencompounds have tautomeric forms, all tautomeric forms are intended to bewithin the scope of the application, and the naming of the compoundsdoes not exclude any tautomer form.

Some compounds of the present application can exist in tautomeric formswhich are also intended to be encompassed within the scope of thepresent application.

The compounds, salts and prodrugs of the present application can existin several tautomeric forms, including the enol and imine form, and theketo and enamine form and geometric isomers and mixtures thereof. Allsuch tautomeric forms are included within the scope of the presentapplication. Tautomers exist as mixtures of a tautomeric set insolution. In solid form, usually one tautomer predominates. Even thoughone tautomer may be described, the present application includes alltautomers of the present compounds

A tautomer is one of two or more structural isomers that exist inequilibrium and are readily converted from one isomeric form to another.This reaction results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Insolutions where tautomerization is possible, a chemical equilibrium ofthe tautomers will be reached. The exact ratio of the tautomers dependson several factors, including temperature, solvent, and pH. The conceptof tautomers that are interconvertable by tautomerizations is calledtautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism, is exhibited by glucose.It arises as a result of the aldehyde group (—CHO) in a sugar chainmolecule reacting with one of the hydroxy groups (—OH) in the samemolecule to give it a cyclic (ring-shaped) form.

Tautomerizations are catalyzed by: Base: 1. deprotonation; 2. formationof a delocalized anion (e.g., an enolate); 3. protonation at a differentposition of the anion; Acid: 1. protonation; 2. formation of adelocalized cation; 3. deprotonation at a different position adjacent tothe cation.

Common tautomeric pairs are: ketone-enol, enamine-imine, lactam-lactim,amide-imidic acid tautomerism in heterocyclic rings (e.g., in thenucleobases guanine, thymine, and cytosine), amine-enamine andenamine-enamine.

It will be noted that the structure of some of the compounds of theapplication include asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers and diastereomers) are included within the scope of theapplication, unless indicated otherwise. Such isomers can be obtained insubstantially pure form by classical separation techniques and bystereochemically controlled synthesis. Furthermore, the structures andother compounds and moieties discussed in this application also includeall tautomers thereof. Alkenes can include either the E- or Z-geometry,where appropriate. The compounds of this application may exist instereoisomeric form, therefore can be produced as individualstereoisomers or as mixtures.

A “pharmaceutical composition” is a formulation containing the disclosedcompounds in a form suitable for administration to a subject. In oneembodiment, the pharmaceutical composition is in bulk or in unit dosageform. The unit dosage form is any of a variety of forms, including, forexample, a capsule, an IV bag, a tablet, a single pump on an aerosolinhaler, or a vial. The quantity of active ingredient (e.g., aformulation of the disclosed compound or salt, hydrate, solvate, orisomer thereof) in a unit dose of composition is an effective amount andis varied according to the particular treatment involved. One skilled inthe art will appreciate that it is sometimes necessary to make routinevariations to the dosage depending on the age and condition of thepatient. The dosage will also depend on the route of administration. Avariety of routes are contemplated, including oral, pulmonary, rectal,parenteral, transdermal, subcutaneous, intravenous, intramuscular,intraperitoneal, inhalational, buccal, sublingual, intrapleural,intrathecal, intranasal, and the like. Dosage forms for the topical ortransdermal administration of a compound of this application includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. In one embodiment, the active compound is mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers, or propellants that are required.

A “subject” includes mammals, e.g., humans, companion animals (e.g.,dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs,horses, fowl, and the like) and laboratory animals (e.g., rats, mice,guinea pigs, birds, and the like). In one embodiment, the subject ishuman.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, carriers, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

The compounds of the application are capable of further forming salts.All of these forms are also contemplated within the scope of the claimedapplication.

“Pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines, alkali or organic salts ofacidic residues such as carboxylic acids, and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic,bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic,lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic,succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluenesulfonic, and the commonly occurring amine acids, e.g., glycine,alanine, phenylalanine, arginine, etc.

Other examples include hexanoic acid, cyclopentane propionic acid,pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamicacid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, andthe like. The application also encompasses salts formed when an acidicproton present in the parent compound either is replaced by a metal ion,e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base such as ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, and the like.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates), as definedherein, of the same salt.

The pharmaceutically acceptable salts of the present application can besynthesized from a parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.Lists of suitable salts are found in Remington's PharmaceuticalSciences, 18th ed. (Mack Publishing Company, 1990). For example, saltscan include, but are not limited to, the hydrochloride and acetate saltsof the aliphatic amine-containing, hydroxyl amine-containing, andimine-containing compounds of the present application.

The compounds of the present application can also be prepared as esters,for example pharmaceutically acceptable esters. For example a carboxylicacid function group in a compound can be converted to its correspondingester, e.g., a methyl, ethyl, or other ester. Also, an alcohol group ina compound can be converted to its corresponding ester, e.g., anacetate, propionate, or other ester.

The compounds of the present application can also be prepared asprodrugs, for example pharmaceutically acceptable prodrugs. The terms“pro-drug” and “prodrug” are used interchangeably herein and refer toany compound which releases an active parent drug in vivo. Sinceprodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present application can be delivered in prodrugform. Thus, the present application is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent application in vivo when such prodrug is administered to asubject. Prodrugs the present application are prepared by modifyingfunctional groups present in the compound in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound. Prodrugs include compounds of the presentapplication wherein a hydroxy, amino, sulfhydryl, carboxy, or carbonylgroup is bonded to any group that, may be cleaved in vivo to form a freehydroxyl, free amino, free sulfhydryl, free carboxy or free carbonylgroup, respectively.

Examples of prodrugs include, but are not limited to, esters (e.g.,acetate, dialkylaminoacetates, formates, phosphates, sulfates, andbenzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl)of hydroxy functional groups, esters groups (e.g. ethyl esters,morpholinoethanol esters) of carboxyl functional groups, N-acylderivatives (e.g., N-acetyl) N-Mannich bases, Schiff bases andenaminones of amino functional groups, oximes, acetals, ketals and enolesters of ketone and aldehyde functional groups in compounds of formulaI, and the like, See Bundegaard, H. “Design of Prodrugs” p 1-92,Elesevier, New York-Oxford (1985).

In the specification, the singular forms also include the plural, unlessthe context clearly dictates otherwise. Unless defined otherwise, alltechnical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisapplication belongs. In the case of conflict, the present specificationwill control.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

“Combination therapy” (or “co-therapy”) includes the administration of acompound of the application and at least a second agent as part of aspecific treatment regimen intended to provide the beneficial effectfrom the co-action of these therapeutic agents. The beneficial effect ofthe combination includes, but is not limited to, pharmacokinetic orpharmacodynamic co-action resulting from the combination of therapeuticagents. Administration of these therapeutic agents in combinationtypically is carried out over a defined time period (usually minutes,hours, days or weeks depending upon the combination selected).“Combination therapy” may, but generally is not, intended to encompassthe administration of two or more of these therapeutic agents as part ofseparate monotherapy regimens that incidentally and arbitrarily resultin the combinations of the present application.

“Combination therapy” is intended to embrace administration of thesetherapeutic agents in a sequential manner, that is, wherein eachtherapeutic agent is administered at a different time, as well asadministration of these therapeutic agents, or at least two of thetherapeutic agents, in a substantially simultaneous manner.Substantially simultaneous administration can be accomplished, forexample, by administering to the subject a single capsule having a fixedratio of each therapeutic agent or in multiple, single capsules for eachof the therapeutic agents. Sequential or substantially simultaneousadministration of each therapeutic agent can be effected by anyappropriate route including, but not limited to, oral routes,intravenous routes, intramuscular routes, and direct absorption throughmucous membrane tissues. The therapeutic agents can be administered bythe same route or by different routes. For example, a first therapeuticagent of the combination selected may be administered by intravenousinjection while the other therapeutic agents of the combination may beadministered orally. Alternatively, for example, all therapeutic agentsmay be administered orally or all therapeutic agents may be administeredby intravenous injection. The sequence in which the therapeutic agentsare administered is not narrowly critical.

“Combination therapy” also embraces the administration of thetherapeutic agents as described above in further combination with otherbiologically active ingredients and non-drug therapies (e.g., surgery orradiation treatment). Where the combination therapy further comprises anon-drug treatment, the non-drug treatment may be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and non-drug treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the non-drug treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where processes are described as having,including, or comprising specific process steps, the processes alsoconsist essentially of, or consist of, the recited processing steps.Further, it should be understood that the order of steps or order forperforming certain actions are immaterial so long as the applicationremains operable. Moreover, two or more steps or actions may beconducted simultaneously.

The compounds, or pharmaceutically acceptable salts thereof, isadministered orally, nasally, transdermally, pulmonary, inhalationally,buccally, sublingually, intraperintoneally, subcutaneously,intramuscularly, intravenously, rectally, intrapleurally, intrathecallyand parenterally. In one embodiment, the compound is administeredorally. One skilled in the art will recognize the advantages of certainroutes of administration.

The dosage regimen utilizing the compounds is selected in accordancewith a variety of factors including type, species, age, weight, sex andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to prevent, counteror arrest the progress of the condition.

Techniques for formulation and administration of the disclosed compoundsof the application can be found in Remington: the Science and Practiceof Pharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa. (1995).In an embodiment, the compounds described herein, and thepharmaceutically acceptable salts thereof, are used in pharmaceuticalpreparations in combination with a pharmaceutically acceptable carrieror diluent. Suitable pharmaceutically acceptable carriers include inertsolid fillers or diluents and sterile aqueous or organic solutions. Thecompounds will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein.

In one embodiment, the compound is prepared for oral administration,wherein the disclosed compounds or salts thereof are combined with asuitable solid or liquid carrier or diluent to form capsules, tablets,pills, powders, syrups, solutions, suspensions and the like.

The tablets, pills, capsules, and the like contain from about 1 to about99 weight percent of the active ingredient and a binder such as gumtragacanth, acacias, corn starch or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch or alginic acid; a lubricant such as magnesium stearate; and/or asweetening agent such as sucrose, lactose, saccharin, xylitol, and thelike. When a dosage unit form is a capsule, it often contains, inaddition to materials of the above type, a liquid carrier such as afatty oil.

In some embodiments, various other materials are present as coatings orto modify the physical form of the dosage unit. For instance, in someembodiments, tablets are coated with shellac, sugar or both. In someembodiments, a syrup or elixir contains, in addition to the activeingredient, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and a flavoring such as cherry or orange flavor,and the like.

For some embodiments relating to parental administration, the disclosedcompounds, or salts, solvates, tautomers or polymorphs thereof, can becombined with sterile aqueous or organic media to form injectablesolutions or suspensions. In one embodiment, injectable compositions areaqueous isotonic solutions or suspensions. The compositions may besterilized and/or contain adjuvants, such as preserving, stabilizing,wetting or emulsifying agents, solution promoters, salts for regulatingthe osmotic pressure and/or buffers. In addition, they may also containother therapeutically valuable substances. The compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1 to 75%, in another embodiment, thecompositions contain about 1 to 50%, of the active ingredient.

For example, injectable solutions are produced using solvents such assesame or peanut oil or aqueous propylene glycol, as well as aqueoussolutions of water-soluble pharmaceutically-acceptable salts of thecompounds. In some embodiments, dispersions are prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms. The terms “parenteraladministration” and “administered parenterally” as used herein meansmodes of administration other than enteral and topical administration,usually by injection, and includes, without limitation, intravenous,intramuscular, intraarterial, intrathecal, intracapsular, intraorbital,intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous,subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal andintrasternal injection and infusion.

For rectal administration, suitable pharmaceutical compositions are, forexample, topical preparations, suppositories or enemas. Suppositoriesare advantageously prepared from fatty emulsions or suspensions. Thecompositions may be sterilized and/or contain adjuvants, such aspreserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure and/or buffers. Inaddition, they may also contain other therapeutically valuablesubstances. The compositions are prepared according to conventionalmixing, granulating or coating methods, respectively, and contain about0.1 to 75%, in another embodiment, compositions contain about 1 to 50%,of the active ingredient.

In some embodiments, the compounds are formulated to deliver the activeagent by pulmonary administration, e.g., administration of an aerosolformulation containing the active agent from, for example, a manual pumpspray, nebulizer or pressurized metered-dose inhaler. In someembodiments, suitable formulations of this type also include otheragents, such as antistatic agents, to maintain the disclosed compoundsas effective aerosols.

A drug delivery device for delivering aerosols comprises a suitableaerosol canister with a metering valve containing a pharmaceuticalaerosol formulation as described and an actuator housing adapted to holdthe canister and allow for drug delivery. The canister in the drugdelivery device has a headspace representing greater than about 15% ofthe total volume of the canister. Often, the polymer intended forpulmonary administration is dissolved, suspended or emulsified in amixture of a solvent, surfactant and propellant. The mixture ismaintained under pressure in a canister that has been sealed with ametering valve.

For nasal administration, either a solid or a liquid carrier can beused. The solid carrier includes a coarse powder having particle size inthe range of, for example, from about 20 to about 500 microns and suchformulation is administered by rapid inhalation through the nasalpassages. In some embodiments where the liquid carrier is used, theformulation is administered as a nasal spray or drops and includes oilor aqueous solutions of the active ingredients.

Also contemplated are formulations that are rapidly dispersing dosageforms, also known as “flash dose” forms. In particular, some embodimentsof the present application are formulated as compositions that releasetheir active ingredients within a short period of time, e.g., typicallyless than about five minutes, in another embodiment, less than aboutninety seconds, in another embodiment, less than about thirty secondsand in another embodiment, in less than about ten or fifteen seconds.Such formulations are suitable for administration to a subject via avariety of routes, for example by insertion into a body cavity orapplication to a moist body surface or open wound.

Typically, a “flash dosage” is a solid dosage form that is administeredorally, which rapidly disperses in the mouth, and hence does not requiregreat effort in swallowing and allows the compound to be rapidlyingested or absorbed through the oral mucosal membranes. In someembodiments, suitable rapidly dispersing dosage forms are also used inother applications, including the treatment of wounds and other bodilyinsults and diseased states in which release of the medicament byexternally supplied moisture is not possible.

“Flash dose” forms are known in the art; see for example, effervescentdosage forms and quick release coatings of insoluble microparticles inU.S. Pat. Nos. 5,578,322 and 5,607,697; freeze dried foams and liquidsin U.S. Pat. Nos. 4,642,903 and 5,631,023; melt spinning of dosage formsin U.S. Pat. Nos. 4,855,326, 5,380,473 and 5,518,730; solid, free-formfabrication in U.S. Pat. No. 6,471,992; saccharide-based carrier matrixand a liquid binder in U.S. Pat. Nos. 5,587,172, 5,616,344, 6,277,406,and 5,622,719; and other forms known to the art.

The compounds of the application are also formulated as “pulsed release”formulations, in which the compound is released from the pharmaceuticalcompositions in a series of releases (i.e., pulses). The compounds arealso formulated as “sustained release” formulations in which thecompound is continuously released from the pharmaceutical compositionover a prolonged period.

Also contemplated are formulations, e.g., liquid formulations, includingcyclic or acyclic encapsulating or solvating agents, e.g.,cyclodextrins, polyethers, or polysaccharides (e.g., methylcellulose),or in another embodiment, polyanionic β-cyclodextrin derivatives with asodium sulfonate salt group separate from the lipophilic cavity by analkyl ether spacer group or polysaccharides. In one embodiment, theagent is methylcellulose. In another embodiment, the agent is apolyanionic β-cyclodextrin derivative with a sodium sulfonate saltseparated from the lipophilic cavity by a butyl ether spacer group,e.g., CAPTISOL® (CyDex, Overland, Kans.). One skilled in the art canevaluate suitable agent/disclosed compound formulation ratios bypreparing a solution of the agent in water, e.g., a 40% by weightsolution; preparing serial dilutions, e.g., to make solutions of 20%,10, 5%, 2.5%, 0% (control), and the like; adding an excess (compared tothe amount that can be solubilized by the agent) of the disclosedcompound; mixing under appropriate conditions, e.g., heating, agitation,sonication, and the like; centrifuging or filtering the resultingmixtures to obtain clear solutions; and analyzing the solutions forconcentration of the disclosed compound.

All publications and patent documents cited herein are incorporatedherein by reference as if each such publication or document wasspecifically and individually indicated to be incorporated herein byreference. Citation of publications and patent documents is not intendedas an admission that any is pertinent prior art, nor does it constituteany admission as to the contents or date of the same. The applicationhaving now been described by way of written description, those of skillin the art will recognize that the application can be practiced in avariety of embodiments and that the foregoing description and examplesbelow are for purposes of illustration and not limitation of the claimsthat follow.

Synthesis of the Compounds of the Application

Compounds of the application can be synthesized according to thefollowing scheme.

Scheme 1 shows the synthesis of some of the claimed compounds followinga general route that utilizes well-established chemistry. Step 1 showsan aromatic substitution reaction involving displacement of a leavinggroup by a nucleophillic carboxylic precursor that can provide thedesired arrangement of the carboxylic precursor. In this example theleaving group is fluoride but could be another leaving group such as ahalogen or an alkoxide. The nucleophillic carboxylic precursor could beacetonitrile, an acetic acid analog, or malonate with inherentnucleophillicity induced by deprotonation with a base such as lithiumhexamethyldisilazide, potassium hexamethyldisilazide, alkyl lithium,lithium diisopropylamide, or a similar base.

Step 2 shows the conversion of the carboxylic precursor to the desiredcarboxylic acid or ester. The carboxylic precursor can be a cyano groupwhich is converted to the desired carboxylic acid or ester by acid orbase catalyzed hydrolysis. The carboxylic precursor can also be amalonate that can be converted to the desired carboxylic acid or esterby acid or base catalyzed hydrolysis and subsequent decarboxylation.

Step 3 shows the conversion of the carboxylic acid or ester to thedesired amide. The carboxylic acid can be converted to the amide byestablished amide coupling techniques facilitated by many establishedreagents such as PyBOP or carbodiimide-based reagents. Alternatively,the amide can be synthesized by heating the amine and ester in a highboiling solvent such as anisole. This same amide coupling reaction canbe conducted with the amine and ester at lower temperature by firstactivating the amine by reaction with trimethyl aluminum followed byaddition of the ester.

Step 4 shows the conversion of the aryl bromide to the boronic ester.This conversion is typically palladium-catalyzed in the presence of aboronate, such as bis(pinocolato)diboron. As an alternative,lithium-halogen exchange followed by a quench with a boronic acid orester can be used to accomplish this conversion.

The formation of the boronate facilitates the bi-aryl coupling by Suzukiconversion with the aryl-LG₂ shown in Step 5. As an alternative, LG₂ canbe converted to the boronate and reacted with the aryl bromide producedby Step 3. The well-established Suzuki reaction, Step 5, is typicallyconducted with a palladium catalyst in the presence of a weak base suchas sodium carbonate, potassium carbonate, or sodium bicarbonate withheating to 80-110° C.

Scheme 2 shows the synthesis of some of the compounds of the presentapplication that belong to formula A, I, II, III, IVa, IVc, IVd, Va, Vb,Vc, Vd, VIa, VIb, VIc, VId, VIIa, VIIb VIIc, VIId, or VIIe following analternative general route that utilizes well-established chemistry. Step1 shows either an aromatic substitution reaction involving displacementof an iodo or bromo group by a substituted cyclic amine or aBuchwald-Hartwig amination. The aromatic substitution can be induced bydeprotonation of the cyclic amine with a base such as lithiumhexamethyldisilazide, potassium hexamethyldisilazide, alkyl lithium,lithium diisopropylamide, or a similar base. Buchwald-Hartwig aminationreactions can be achieved using palladium catalyst, such as palladiumacetate, in the presence of phosphine ligand, such as tri(o-tolylphosphine) or racemic BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl), and a base, such assodium or potassium tert-butoxide.

Step 2 involves bi-aryl coupling by Suzuki conversion of the arylbromide obtained from step 1 with aryl boronic acid or ester. The Suzukireaction is typically conducted with a palladium catalyst in thepresence of a weak base such as sodium carbonate, potassium carbonate,or sodium bicarbonate with heating at 80-110° C.

Step 3 shows an aromatic substitution reaction involving displacement ofa leaving group by a nucleophillic carboxylic precursor that can providethe desired arrangement of the carboxylic precursor. In this example theleaving group is fluoride but could be another leaving group such as ahalogen or an alkoxide, depending on the boronic acid or ester used instep 2. The nucleophillic carboxylic precursor could be acetonitrile,acetic acid analog, or malonate with inherent nucleophillicity inducedby deprotonation with a base such as lithium hexamethyldisilazide,potassium hexamethyldisilazide, alkyl lithium, lithium diisopropylamide,or a similar base.

Step 4 shows the conversion of the carboxylic precursor to the desiredcarboxylic acid. The carboxylic precursor can be a cyano group which isconverted to the desired carboxylic acid by acid or base catalyzedhydrolysis. The carboxylic precursor can also be a malonate that can beconverted to the desired carboxylic acid by acid or base catalyzedhydrolysis and subsequent decarboxylation.

Step 5 shows the conversion of the carboxylic acid or ester to thedesired amide, which is the final product. The carboxylic acid can beconverted to the amide by reacting with an amine and PyBOP(benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) ora carbodiimide-based reagent.

General Assays

The activity of the compounds of the application can be tested in assaysknown in the art. For example, the drug concentration required to blocknet cell growth by 50% relative to a control sample can be measured asthe GI₅₀.

For example, in an MTT assay, the U87 and GL261 cells is seeded in96-well plate (e.g., 6×10³ cells in 100 μl of DMEM+10% FBS media perwell) and incubated overnight at about 30-40° C. with about 2-10% CO₂.All test compounds is diluted (10 point 2-fold serial dilution) in aseparate 96-well plate to yield 10× of final the concentrations (e.g.,0.5-256 nM). A volume of about 11 μl of 10× dilutions is added toappropriate wells (n=3). To value (reflecting the starting number ofcells upon drug treatment) can be determined by following steps asdescribed below. After 3 days incubation at about 30-40° C. with about2-10% CO₂, about 10 μl of MTT solution (e.g., 5 mg/ml in PBS) is addedto each well and plates are incubated at about 30-40° C. for about 2-6 hto allow MTT to form formazan crystals by reacting with metabolicallyactive cells. About 100 μl of 20% SDS is added to each well and platesare incubated overnight at about 30-40° C. with 5% CO₂. Afterward, OD₅₇₀is measured using microplate reader. The cell growth percentage ofcontrol is calculated according to percentage ofcontrol=(T-T₀)/(C-T₀)×100% or OD value of the test well exposure to testdrug−OD value at time zero/(OD of the control well without drugtreatment−OD value at time zero)×100%. Growth inhibition curves and GI₅₀are determined using GraphPad Prism 5 software.

EXAMPLES Example 1: Syntheses

Preparation of Compound 100

Synthesis of

Under a rapid stream of nitrogen, a suspension of potassiumbis(trimethylsilyl)amide (41.58 g, 0.208 mol) in 100 ml of anhydrous THFwas prepared in a 500 ml round-bottomed flask equipped with a stir bar.The suspension was cooled using an ice/methanol bath and a solution ofanhydrous MeCN (7.00 g, 0.170 mol) in anhydrous THF (11 ml) was slowlyadded to the suspension (over a period of 3-5 min). This was followed bythe rapid addition of a solution of 2-fluoro-5-bromopyridine (4.93 g,0.0280 mol) in anhydrous THF (40 ml). The reaction mixture was stirredunder nitrogen for 2-3 hours, and checked by LCMS for the completeconsumption of the starting material. Upon reaction completion EtOAc(500 ml) was added. The solution was washed twice with saturated brine(250 ml), and dried with anhydrous Na₂SO₄. Anhydrous Na₂SO₄ was filteredoff, and the organic solution was concentrated in vacuo to give aresidual red oily substance. This oily material was dissolved in EtOAc(25 ml), adsorbed on silica gel, and purified with flash chromatographyusing heptanes: EtOAc as a mobile phase to give Compound 1 as red oil(4.03 g, yield: 73%). Purity by HPLC (UV 254 nm) found to be >90%; LCMS:(198/200[M+H]⁺). ¹H NMR (400 MHz, CDCl₃): 3.91 (s, 2H), 7.35 (d, 1H),7.88 (dd, 1H), 8.64 (fine d, 1H).

Synthesis of

A single-necked round-bottomed flask was charged with Compound 1 (4.55g, 23.1 mmol) and MeOH (40 g) followed by the dropwise addition of 96%H₂SO₄ (28 g). The resulting homogeneous solution stirred at reflux (115°C. oil bath) until the reaction was complete by TLC. After briefcooling, MgSO₄ (9 g) was added and the mixture swirled and allowed tostand an additional 45 min. The reaction mixture was then added slowlyto a rapidly stirred and cooled (ice-water bath) mixture of DCM (250 mL)and a solution of K₂CO₃ (50 g) in H₂O (70 mL). The resulting emulsionwas allowed to stand overnight. The clear portions of organic solutionwere siphoned off and the remainder portions were treated iterativelywith water and DCM, the clear organics being combined with the originalportion that was siphoned off. The combined organics were dried(Na₂SO₄), filtered, concentrated, and purified by silica gelchromatography. The desired product, Compound 2, was obtained as acolorless solid (3.82 g, 72% yield) and characterized by LCMS(230.7[M+H]⁺).

Synthesis of

A single-necked round-bottomed flask was charged with Compound 2 (1.80g, 7.82 mmol), 3-fluorobenzylamine (2.94 g, 23.5 mmol), and anhydrousanisole (15 g). The reaction was stirred at 150° C. until reaction wascomplete LCMS (˜23 h) and then allowed to cool to near RT. Crystals ofthe desired product, Compound 3, formed during the cooling process andwere collected by filtration and washed with toluene. Compound 3 wasobtained as colorless crystalline solid (1.59 g, 63% yield) andcharacterized by ¹H NMR (400 MHz, DMSO-d₆): 3.69 (s, 2H), 4.30 (d, 2H),7.0-7.15 (m, 3H), 7.3-7.4 (m, 2H), 7.99 (dd, 1H), 8.61 (fine d, 1H),8.66 (br t, 1H).

Synthesis of

In a single-neck round bottom flask Compound 3 (292 mg, 0.904 mmol),bis(pinacolato)diboron (729 mg, 2.87 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (39 mg, 0.0479 mmol), and potassium acetate (234mg, 2.39 mmol) were combined neat. The flask was equipped with acondenser, sealed, and purged with nitrogen. Anhydrous 1,4-dioxane wasadded and the reaction was refluxed for 24 hr. The reaction was cooledand solvent removed in vacuo. The residue was taken up in DCM and washedtwice with 0.5N NaOH and twice with brine. The organic layer was driedwith sodium sulfate and concentrated. This provided crude Compound 4(378 mg) as a dark brown tar which was characterized by LCMS(371[M+H]⁺).

Synthesis of

In a microwave vial 2-S-methylmorpholine (120 mg, 1.19 mmol),4-iodo-bromobenzene (336 mg, 1.19 mmol),bis(dibenzylideneacetone)palladium (54 mg, 0.059 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (48 mg, 0.119mmol), and sodium tert-butoxide (340 mg, 3.56 mmol) were combined neat.The vial was sealed and purged with nitrogen. Anhydrous toluene (2 mL),degassed with nitrogen purge, was added to the vial. The reaction washeated at 100° C. for 30 minutes in a microwave reactor. LCMS indicatedcomplete consumption of the 4-iodo-bromobenzene. The reaction solventwas removed in vacuo and the residue was purified by preparative HPLC.The desired product, Compound 5, was obtained (69 mg, 23% yield,colorless oil) and characterized by LCMS (256/258[M+H]⁺) and ¹H NMR (400MHz, DMSO): 1.11 (s, 3H), 2.27 (dd, 10.4, 11.2 hz, 1H), 2.59 (td 3.6,11.2 Hz, 1H), 3.30 (d, 17.2 Hz, 1H), 3.50-3.65 (m, 3H), 3.85-3.90 (m,1H), 6.87 (d, 8.8 Hz, 2H), 7.32 (d, 8.8 Hz, 2H).

Synthesis of

Compound 4 (230 mg, 0.625 mmol), Compound 5 (64 mg, 0.25 mmol), andtetrakis(triphenylphosphine)-palladium(0) (14 mg, 0.0125 mmol) werecombined neat in a reaction vial that was capped and purged withnitrogen. 1,2-Dimethoxyethane (1.5 mL, purged with nitrogen) and 2Msodium carbonate (0.5 mL, purged with nitrogen) were added to thereaction. The reaction was stirred and heated at 80° C. for 3 hours.LCMS indicated complete consumption of Compound 5. The reaction solventwas removed in vacuo and the residue was purified by preparative HPLC.The desired product, Compound 6, was obtained (43 mg, yellow solid) andcharacterized by LCMS (420 [M+H]⁺). A small aliquot (10 mg) of theproduct was taken up in DCM, washed with saturated sodium bicarbonate,and dried with sodium sulfate. The DCM was removed in vacuo to providethe desired product, Compound 100, as the free base (7 mg, colorlesssolid) and characterized by LCMS (420[M+H]⁺) and melting point (154-155°C.).

Preparation of Compound 101

Synthesis of

In a microwave vial 2-R-methylmorpholine hydrochloride (250 mg, 1.82mmol), 4-iodo-bromobenzene (514 mg, 1.82 mmol,bis(dibenzylideneacetone)palladium (83 mg, 0.09 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (72 mg, 0.0182mmol), and sodium tert-butoxide (700 mg, 7.28 mmol) were combined neat.The vial was sealed and purged with nitrogen. Anhydrous toluene (4 mL,degassed with nitrogen purge) was added to the vial. The reaction washeated at 100° C. for 30 minutes in a microwave reactor. LCMS indicatedcomplete consumption of the 4-iodo-bromobenzene. The reaction solventwas removed in vacuo and the residue was purified by preparative HPLC.The desired product, Compound 7, was obtained (244 mg, 52% yield) as acolorless oil and characterized by LCMS (256/258[M+H]⁺).

Synthesis of

Compound 4 (60 mg, 0.162 mmol), Compound 7 (23 mg, 0.090 mmol), andtetrakis(triphenylphosphine)-palladium(0) (5 mg, 0.005 mmol) werecombined neat in a reaction vial that was capped and purged withnitrogen. 1,2-Dimethoxyethane (1.5 mL, purged with nitrogen) and 2Msodium carbonate (0.5 mL, purged with nitrogen) were added to thereaction. The reaction was stirred and heated at 95° C. for 3 hours.LCMS indicated complete consumption of Compound 7. The reaction solventwas removed in vacuo, the residue was taken up in EtOAc, and washed withsaturated sodium bicarbonate. The EtOAc was removed in vacuo and theresidue was purified by preparative HPLC. The product was taken up inDCM, washed with saturated sodium bicarbonate, and dried with sodiumsulfate. The DCM was removed in vacuo to provide the desired product,Compound 101 (5 mg, 14% yield, colorless solid) and characterized byLCMS (420[M+H]⁻) and melting point (164-166° C.).

Preparation of Compound 102

Synthesis of

In a microwave vial 3-S-methylmorpholine (120 mg, 1.19 mmol),4-iodo-bromobenzene (336 mg, 1.19 mmol,bis(dibenzylideneacetone)palladium (54 mg, 0.059 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (48 mg, 0.119mmol), and sodium tert-butoxide (340 mg, 3.56 mmol) were combined neat.The vial was sealed and purged with nitrogen. Anhydrous toluene (2 mL),degassed with nitrogen purge, was added to the vial. The reaction washeated at 100° C. for 30 minutes in a microwave reactor. LCMS indicatedcomplete consumption of the 4-iodo-bromobenzene. The reaction solventwas removed in vacuo and the residue was purified by preparative HPLC.The desired product, Compound 9, was obtained (64 mg, colorless oil) andcharacterized by LCMS (256/258[M+H]⁺).

Synthesis of

Compound 4 (107 mg, 0.288 mmol), Compound 9 (64 mg, 0.25 mmol), andtetrakis(triphenylphosphine)-palladium(0) (15 mg, 0.0125 mmol) werecombined neat in a reaction vial that was capped and purged withnitrogen. 1,2-Dimethoxyethane (1.5 mL, purged with nitrogen) and 2Msodium carbonate (0.5 mL, purged with nitrogen) were added to thereaction. The reaction was stirred and heated at 95° C. for 3 hours.LCMS indicated complete consumption of Compound 9. The reaction solventwas removed in vacuo, the residue was taken up in EtOAc, and washed withsaturated sodium bicarbonate. The EtOAc was removed in vacuo and theresidue was purified by preparative HPLC. The product was taken up inDCM, washed with saturated sodium bicarbonate, and dried with sodiumsulfate. The DCM was removed in vacuo to provide the desired product,Compound 102 was obtained (16 mg, 15% yield, colorless solid) andcharacterized by LCMS (420[M+H]⁺) and melting point (165-167° C.).

Preparation of Compound 103

Synthesis of

In a microwave vial 3-R-methylmorpholine (250 mg, 2.50 mmol),4-iodo-bromobenzene (699 mg, 2.50 mmol,bis(dibenzylideneacetone)palladium (113 mg, 0.125 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (97 mg, 0.250mmol), and sodium tert-butoxide (715 mg, 7.50 mmol) were combined neat.The vial was sealed and purged with nitrogen. Anhydrous toluene (5 mL,degassed with nitrogen purge) was added to the vial. The reaction washeated at 90° C. for 18 hr. LCMS indicated complete consumption of the4-iodo-bromobenzene. The reaction solvent was removed in vacuo and theresidue was taken up in DCM. The solution was filtered through a plug ofsilica gel, concentrated, and purified by preparative HPLC. The desiredproduct, Compound 11, was obtained (144 mg, 23% yield, colorless oil)and characterized by LCMS (256/258[M+H]⁺).

Synthesis of

Compound 4 (152 mg, 0.426 mmol), Compound 11 (72 mg, 0.284 mmol), andtetrakis(triphenylphosphine)-palladium(0) (16 mg, 0.0142 mmol) werecombined neat in a reaction vial that was capped and purged withnitrogen. 1,2-Dimethoxyethane (1.5 mL, purged with nitrogen) and 2Msodium carbonate (0.5 mL, purged with nitrogen) were added to thereaction. The reaction was stirred and heated at 95° C. for 3 hours.LCMS indicated complete consumption of Compound 11. The reaction solventwas removed in vacuo, the residue was taken up in EtOAc, and washed withsaturated sodium bicarbonate. The EtOAc was removed in vacuo and theresidue was purified by preparative HPLC. The product was taken up inDCM, washed with saturated sodium bicarbonate, and dried with sodiumsulfate. The DCM was removed in vacuo to provide the desired product,Compound 103 was obtained (27 mg, 23% yield, colorless solid) andcharacterized by LCMS (420[M+H]⁻) and melting point (148-151° C.).

Preparation of Compound 104

Synthesis of

In a dry 500 ml round-bottomed flask (equipped with a water-cooledcondenser, a gas outlet, and a stir bar) palladium acetate (0.449 g,2.00 mmol), tri(o-tolyl)phosphine (1.22 g, 4.00 mmol), and potassiumtert-butoxide (11.2 g, 100 mmol) were combined. The apparatus wassealed, purged with nitrogen, and 60 mL anhydrous toluene was added. Tothe resulting suspension 3-S-methylmorpholine (4.04 g, 40.0 mmol), and2,5-dibromotoluene (12.5 g, 50.0 mmol) dissolved in 30 ml anhydroustoluene were added. The mixture was then stirred and refluxed at anoil-bath temperature of 90-100° C. for 3 days (The system was purgedwith nitrogen every 6-12 hours). The reaction mixture was cooled to roomtemperature, filtered, diluted with 250 ml EtOAc, and concentrated invacuo providing an oily residue. This residue was then dissolved in 30ml EtOAc, adsorbed on silica gel, and purified by flash chromatography(gradient method starting with 100% heptanes up to 40:60% EtOAc:heptanes) to provide Compound 13 as a yellowish oil (1.4 g, 13% yield).LCMS (270/272: [M+H]⁺), ¹H NMR (400 MHz, MeOD): 1.02 (d, J=6.5 Hz, 3H),2.32 (s, 3H), 3.06 (m, 2H), 3.60-3.80 (m, 4H) 3.90 (m, 1H) 6.65 (dd,J=7.0, 2.5 Hz, 1H) 6.84 (d, J=2.5 Hz, 1H) 7.35 (d, J=7 Hz, 1H); COSY andNOESY studies confirmed that the desired regioisomer was obtained.

Synthesis of

In a dry 500 ml round-bottomed flask (equipped with a water-cooledcondenser, a gas outlet, and a stir bar) palladium acetate (0.337 g, 1.5mmol), tri(o-tolyl)phosphine (0.912 g, 2.98 mmol), and potassiumtert-butoxide (8.41 g, 75 mmol) were combined. The apparatus was sealed,purged with nitrogen, and 45 mL anhydrous toluene was added. To theresulting suspension 3-R-methylmorpholine (3.03 g, 30 mmol), and2,5-dibromotoluene (9.38 g, 37.5 mmol) dissolved in 23 ml anhydroustoluene were added. The mixture was then stirred and refluxed at anoil-bath temperature of 90-100° C. for 3 days (The system was purgedwith nitrogen every 6-12 hours). The reaction mixture was cooled to roomtemperature, filtered, diluted with 250 ml EtOAc, and concentrated invacuo providing an oily residue. This residue was then dissolved in 30ml EtOAc, adsorbed on silica gel, and purified by flash chromatography(gradient method starting with 100% heptanes up to 40:60% EtOAc:heptanes) to provide Compound 14 as a yellowish oil (890 mg; 11% yield).LCMS (270/272: [M+H]⁺), ¹H NMR (400 MHz, MeOD): 1.02 (d, J=6.5 Hz, 3H),2.32 (s, 3H), 3.06 (m, 2H), 3.60-3.80 (m, 4H) 3.90 (m, 1H) 6.65 (dd,J=7.0, 2.5 Hz, 1H) 6.84 (d, J=2.5 Hz, 1H) 7.35 (d, J=7 Hz, 1H).

Synthesis of

In a 50 ml round-bottomed flask equipped with a stir bar, and connectedto a water-cooled condenser, Compound 13 (1.35 g, 5.00 mmol),2-fluoropyridine-5-boronic acid (1.06 g, 7.50 mmol), and tetrakis(triphenylphosphine)-palladium(0) (312 mg, 0.270 mmol) were dissolved in15 ml 1,4-dioxane and 5 ml of 4M aqueous sodium carbonate solution. Thereaction mixture was then stirred, and refluxed at an oil-bathtemperature of 90° C. for 24 hours. LCMS indicated a complete reaction.The reaction was cooled to room temperature, and diluted with 100 mlEtOAc. The reaction mixture was then washed with 100 ml water and twicewith 50 mL brine. The organic layer was dried with anhydrous sodiumsulfate, filtered, and concentrated in vacuo to give an oily residuewhich was purified by flash chromatography. Compound 15 was obtained asa yellow crystalline solid (1.1 g, 77% yield). LCMS (287 [M+H]⁺). ¹H NMR(400 MHz, DMSO): 0.99 (d, J=8.0 Hz, 3H), 2.18 (s, 3H), 2.95 (m, 1H),3.10 (m, 1H) 3.55 (m, 1H) 3.68 (m, 2H) 3.90 (m, 2H) 6.78 (m, 2H) 7.08(d, J=7 Hz, 1H) 7.20 (dd, J=7.0, 2.5 Hz, 1H) 7.92 (m, 1H) 8.16 (d, J=2.5Hz, 1H).

Synthesis of

In a 50 ml round-bottomed flask equipped with a stir bar, and connectedto a water-cooled condenser, Compound 14 (810 mg, 3.00 mmol),2-fluoropyridine-5-boronic acid (636 mg, 4.50 mmol), and tetrakis(triphenylphosphine)-palladium(0) (187 mg, 0.162 mmol) were dissolved in9 ml 1,4-dioxane and 3 ml of 4M aqueous sodium carbonate. The reactionmixture was then stirred, and refluxed at an oil-bath temperature of 90°C. for 24 hours. LCMS indicated a complete reaction. The reaction wascooled to room temperature and diluted with 60 ml EtOAc. The reactionmixture was then washed with 60 ml water, and twice with 30 mL brine.The organic layer was dried with anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give an oily residue which was purified byflash chromatography to provide Compound 16 (629 mg, 73% yield). LCMS(287 [M+H]⁻). ¹H NMR (400 MHz, DMSO): 0.99 (d, J=8.0 Hz, 3H), 2.18 (s,3H), 2.95 (m, 1H), 3.10 (m, 1H) 3.55 (m, 1H) 3.68 (m, 2H) 3.90 (m, 2H)6.78 (m, 2H) 7.08 (d, J=7 Hz, 1H) 7.20 (dd, J=7.0, 2.5 Hz, 1H) 7.92 (m,1H) 8.16 (d, J=2.5 Hz, 1H).

Synthesis of

Under a rapid stream of nitrogen, a suspension of potassiumbis(trimethylsilyl)amide (5.41 g, 27.1 mmol) in 13 ml anhydrous THF wasprepared in a 50 ml round-bottomed flask equipped with a stir bar. Thesuspension was cooled using an ice/methanol bath and a solution ofanhydrous MeCN (910 mg) in anhydrous THF (1.5 ml) was slowly added (overa period of 3-5 min) to the suspension. This was followed by the rapidaddition of a solution of Compound 15 (1.04 g, 3.64 mmol) in anhydrousTHF (5.5 ml). The reaction mixture was stirred under nitrogen for 2-3hours, and monitored by LCMS for the complete consumption of thestarting material. Upon reaction completion EtOAc (60 ml) was added andwashed twice with saturated brine (30 ml). The organic layer was driedwith anhydrous Na₂SO₄, filtered, and concentrated in vacuo to provide ared oil. This oil was dissolved in EtOAc (10 ml), adsorbed on silicagel, and purified with flash chromatography using heptanes: EtOAc as amobile phase to provide Compound 17 as red oil (793 mg, 71% yield).LCMS: (308 [M+H]⁺). ¹H NMR (400 MHz, DMSO): 0.99 (d, J=8.0 Hz, 3H), 2.19(s, 3H), 2.98 (m, 1H), 3.21 (m, 1H) 3.51 (m, 1H) 3.66 (m, 2H) 3.88 (m,2H) 4.20 (s, 2H) 6.80 (m, 2H) 7.10 (d, J=7 Hz, 1H) 7.40 (d, J=7 Hz, 1H)7.79 (dd, J=7.0, 2.5 Hz, 1H) 8.48 (d, J=2.5 Hz, 1H).

Synthesis of

Under a rapid stream of nitrogen, a suspension of potassiumbis(trimethylsilyl)amide (3.25 g, 16.2 mmol) in 8 ml anhydrous THF wasprepared in a 50 ml round-bottomed flask equipped with a stir bar. Thesuspension was cooled using an ice/methanol bath and a solution ofanhydrous MeCN (550 mg) in anhydrous THF (1.5 ml) was slowly added (overa period of 3-5 min) to the suspension. This was followed by the rapidaddition of a solution of Compound 16 (623 mg, 2.18 mmol) in anhydrousTHF (3.5 ml). The reaction mixture was stirred under nitrogen for 4hours and monitored by LCMS for the complete consumption of the startingmaterial. Upon reaction completion EtOAc (60 ml) was added and themixture was washed twice with saturated brine (30 ml). The organic layerwas dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo toprovide a red oil. This oil was dissolved in EtOAc (10 ml), adsorbed onsilica gel, and purified with flash chromatography using heptanes: EtOAcas a mobile phase to provide Compound 18 as red oil (436 mg, 65% yield).LCMS: (308[M+H]⁺). ¹H NMR (400 MHz, DMSO): 0.99 (d, J=8.0 Hz, 3H), 2.19(s, 3H), 2.98 (m, 1H), 3.21 (m, 1H) 3.51 (m, 1H) 3.66 (m, 2H) 3.88 (m,2H) 4.20 (s, 2H) 6.80 (m, 2H) 7.10 (d, J=7 Hz, 1H) 7.40 (d, J=7 Hz, 1H)7.79 (dd, J=7.0, 2.5 Hz, 1H) 8.48 (d, J=2.5 Hz, 1H).

Synthesis of

Compound 17 (750 mg, 2.44 mmol) was slowly added to an ice-cooled 10 ml37% hydrochloric acid in a 50 ml round-bottomed flask equipped with astir bar. Each addition was accompanied by shaking the flask in order todissolve the solid. The round-bottomed flask was equipped with awater-cooled condenser. The reaction mixture was stirred and heated to65-70° C. for 3 hours. The reaction was monitored by LCMS. Upon reactioncompletion the mixture was cooled to room temperature, and the solutionwas concentrated in vacuo to provide crude Compound 19 as a yellowsolid. LCMS: (327[M+H]⁺, 325[M−H]⁻).

Synthesis of

Compound 17 (430 mg, 1.3 mmol) was slowly added to an ice-cooled 10 ml37% hydrochloric acid in a 50 ml round-bottomed flask equipped with astir bar. Each addition was accompanied by shaking the flask in order todissolve the solid. The round-bottomed flask was then connected to awater-cooled condenser. The reaction mixture was stirred, and heated to65-70° C. for 3 hours. The reaction was monitored by LCMS. Upon reactioncompletion the mixture was cooled to room temperature, and the solutionwas concentrated in vacuo to provide crude Compound 20 as a yellowsolid. LCMS: (327[M+H]⁺, 325[M−H]⁻).

Synthesis of

In a 40 ml vial equipped with a stir bar Compound 19 (350 mg, 1.00 mmol)and HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (380 mg, 1.00 mmol) were dissolved in 3 mlof a mixture of DMF:water (2:1). A solution of benzylamine (107 mg, 1.00mmol) and diisopropylethylamine (0.66 ml, 5.0 mmol) in 5 ml DMF was thenadded to Compound 19 solution at 0-5° C. The mixture was then stirred atroom temperature overnight, and the reaction was checked for completionusing LCMS. Upon reaction completion, the mixture was diluted with EtOAc(60 ml), washed with water (60 ml), and saturated brine solution (60 ml)twice. The organic layer was dried using anhydrous sodium sulfate, andthe EtOAc was concentrated in vacuo after filtering the sodium sulfateoff. The resulting residue was dissolved in 20 ml EtOAc, adsorbed tosilica gel, and purified by flash chromatography. Compound 104 wasobtained as a yellow solid (155 mg, 47% yield). The product wascharacterized by LCMS (416[M+H]⁺; purity was estimated to be >95%), and¹H NMR (400 MHz, DMSO): 0.99 (d, J=8.0 Hz, 3H), 2.20 (s, 3H), 2.98 (m,1H), 3.20 (m, 1H) 3.50 (m, 1H) 3.60-3.70 (m, 4H) 3.90 (m, 2H) 4.28 (d,2H) 6.80 (m, 2H) 7.08 (d, J=7 Hz, 1H) 7.20-7.40 (m, 6H) 7.65 (dd, J=7.0,2.5 Hz, 1H) 8.40 (d, J=2.5 Hz, 1H) 8.60 (t, 1H). Meting point was foundto be 106-108° C.

Preparation of Compound 105

In a 40 ml vial equipped with a stir bar Compound 20 (350 mg, 1.00mmol), and HATU (380 mg, 1.00 mmol) were dissolved in 3 ml of a mixtureof DMF:water (2:1). A solution of benzylamine (107 mg, 1.00 mmol) anddiisopropylethylamine (0.66 ml, 5.00 mmol) in 5 ml DMF was then added toCompound 20 solution at 0-5° C. The mixture was then stirred at roomtemperature overnight, and the reaction was checked for completion usingLCMS. Upon reaction completion, the mixture was diluted with EtOAc (60ml), washed with water (60 ml), and saturated brine solution (60 ml)twice. The organic layer was dried using anhydrous sodium sulfate, andthe EtOAc was concentrated in vacuo after filtering the sodium sulfateoff. The resulting residue was dissolved in 20 ml EtOAc, adsorbed tosilica gel, and purified by flash chromatography. Compound 105 wasobtained as a yellow solid (225 mg, 68% yield). The product wascharacterized by LCMS (416[M+H]⁺; purity was estimated to be >95%), and¹H NMR (400 MHz, DMSO): 0.99 (d, J=8.0 Hz, 3H), 2.20 (s, 3H), 2.98 (m,1H), 3.20 (m, 1H) 3.50 (m, 1H) 3.60-3.70 (m, 4H) 3.90 (m, 2H) 4.28 (d,2H) 6.80 (m, 2H) 7.08 (d, J=7 Hz, 1H) 7.20-7.40 (m, 6H) 7.65 (dd, J=7.0,2.5 Hz, 1H) 8.40 (d, J=2.5 Hz, 1H) 8.60 (t, 1H). Meting point was foundto be 98-100° C.

Preparation of Compound 106

In a 40 ml vial equipped with a stir bar Compound 19 (350 mg, 1.00 mmol)and HATU (380 mg, 1.00 mmol) were dissolved in 3 ml of a mixture ofDMF:water (2:1). A solution of 3-fluorobenzylamine (125 mg, 1.00 mmol)and diisopropyl ethylamine (0.66 ml, 5.00 mmol) in 5 ml DMF was thenadded to Compound 19 solution at 0-5° C. The mixture was then stirred atroom temperature overnight, and the reaction was checked for completionusing LCMS. Upon reaction completion, the mixture was diluted with EtOAc(60 ml), washed with water (60 ml), and saturated brine solution (60 ml)twice. The organic layer was dried using anhydrous sodium sulfate, andthe EtOAc was concentrated in vacuo after filtering the sodium sulfateoff. Oily residue was obtained which was dissolved in 20 ml EtOAc,applied to silica gel and purified by flash chromatography. Compound 106was obtained as a yellow solid (165 mg, 48% yield). The product wascharacterized by LCMS (434[M+H]⁺; purity was estimated to be >95%), and¹H NMR (400 MHz, DMSO): 0.99 (d, J=8.0 Hz, 3H), 2.20 (s, 3H), 2.98 (m,1H), 3.20 (m, 1H) 3.54 (m, 1H) 3.60-3.75 (m, 4H) 3.87 (m, 2H) 4.30 (d,2H) 6.80 (m, 2H) 7.08 (d, J=7 Hz, 1H) 7.00-7.10 (m, 4H) 7.30-7.40 (m,2H) 7.65 (dd, J=7.0, 2.5 Hz, 1H) 8.40 (d, J=2.5 Hz, 1H) 8.65 (t, 1H).

Preparation of Compound 107

In a 40 ml vial equipped with a stir bar, Compound 19 (328 mg, 1.00 mmolof this compound) and HATU (380 mg, 1.00 mmol) were dissolved in 3 ml ofa mixture of DMF:water (2:1). A solution of R-(−)-1-aminoindane (133 mg,1.00 mmol) and diisopropylethylamine (0.66 ml, 5.00 mmol) in 5 ml DMFwas then added to Compound 19 solution at 0-5° C. The mixture was thenstirred at room temperature overnight, and the reaction was checked forcompletion using LCMS. Upon reaction completion, the mixture was dilutedwith EtOAc (60 ml), washed with water (60 ml), and saturated brinesolution (60 ml) twice. The organic layer was dried using anhydroussodium sulfate, and the EtOAc was concentrated in vacuo after filteringthe sodium sulfate off. The residue was dissolved in 20 ml EtOAc,adsorbed on to silica gel, and purified by flash chromatography.Compound 107 was obtained as a dark yellow solid (208 mg, 63% yield).Compound 107 was characterized by LCMS (434[M+H]⁺; and purity wasestimated to be 90%).

Preparation of Compound 117

In a 40 ml vial equipped with a stir bar, compound 19 (70 mg, 0.20 mmol)and HATU (95 mg, 0.25 mmol) were dissolved in 3 ml of a mixture ofDMF:water (2:1). A solution of 4-aminomethyl pyridine (27 mg, 0.25 mmol)and diisopropylethylamine (0.17 ml, 1.00 mmol) was then added tocompound 19 solution at 0-5° C. The mixture was then stirred at roomtemperature overnight. Upon the completion of the reaction, the mixturewas diluted with EtOAc (50 ml), and then washed with water and brine (50ml of each). The organic layer was then dried over anhydrous sodiumsulfate, and the EtOAc was evaporated under vacuum. The residue was thenpurified by flash chromatography to give 45 mg of the product (yield:54%). Compound 117 was characterized by LCMS (417 [M+H]⁺; and purity wasestimated to be 90%).

Preparation of Compound 118

In a 40 ml vial equipped with a stir bar, compound 19 (70 mg, 0.20 mmol)and HATU (95 mg, 0.25 mmol) were dissolved in 3 ml of a mixture ofDMF:water (2:1). A solution of 3-aminomethyl pyridine (27 mg, 0.25 mmol)and diisopropylethylamine (0.17 ml, 1.00 mmol) was then added tocompound 19 solution at 0-5° C. The mixture was then stirred at roomtemperature overnight. Upon the completion of the reaction, the mixturewas diluted with EtOAc (50 ml), and then washed with water and brine (50ml of each). The organic layer was then dried over anhydrous sodiumsulfate, and the EtOAc was evaporated under vacuum. The residue was thenpurified by flash chromatography to give 42 mg of the product (yield:50%); Compound 118 was characterized by LCMS (417 [M+H]⁺; and purity wasestimated to be 90%).

Preparation of Compound 119

In a 40 ml vial equipped with a stir bar, compound 19 (70 mg, 0.20 mmol)and HATU (95 mg, 0.25 mmol) were dissolved in 3 ml of a mixture ofDMF:water (2:1). A solution of 2-aminomethyl pyridine (27 mg, 0.25 mmol)and diisopropylethylamine (0.17 ml, 1.00 mmol) was then added tocompound 19 solution at 0-5° C. The mixture was then stirred at roomtemperature overnight. Upon the completion of the reaction, the mixturewas diluted with EtOAc (50 ml), and then washed with water and brine (50ml of each). The organic layer was then dried over anhydrous sodiumsulfate, and the EtOAc was evaporated under vacuum. The residue was thenpurified by flash chromatography to give 49 mg of the product (yield:59%); Compound 119 was characterized by LCMS (417 [M+H]⁺; and purity wasestimated to be 90%).

Preparation of Compound 120

In a 40 ml vial equipped with a stir bar, compound 19 (70 mg, 0.20 mmol)and HATU (95 mg, 0.25 mmol) were dissolved in 3 ml of a mixture ofDMF:water (2:1). A solution of 2-fluorobenzylamine (31 mg, 0.25 mmol)and diisopropylethylamine (0.17 ml, 1.00 mmol) was then added tocompound 19 solution at 0-5° C. The mixture was then stirred at roomtemperature overnight. Upon the completion of the reaction, the mixturewas diluted with EtOAc (50 ml), and then washed with water and brine (50ml of each). The organic layer was then dried over anhydrous sodiumsulfate, and the EtOAc was evaporated under vacuum. The residue was thenpurified by flash chromatography to give 40 mg of the product (yield:46%); Compound 120 was characterized by LCMS (434 [M+H]⁺; and purity wasestimated to be 95%).

Preparation of Compound 121

In a 40 ml vial equipped with a stir bar, compound 19 (70 mg, 0.20 mmol)and HATU (95 mg, 0.25 mmol) were dissolved in 3 ml of a mixture ofDMF:water (2:1). A solution of 4-fluorobenzylamine (31 mg, 0.25 mmol)and diisopropylethylamine (0.17 ml, 1.00 mmol) was then added tocompound 19 solution at 0-5° C. The mixture was then stirred at roomtemperature overnight. Upon the completion of the reaction, the mixturewas diluted with EtOAc (50 ml), and then washed with water and brine (50ml of each). The organic layer was then dried over anhydrous sodiumsulfate, and the EtOAc was evaporated under vacuum. The residue was thenpurified by flash chromatography to give 51 mg of the product (yield:59%); Compound 121 was characterized by LCMS (434 [M+H]⁺; and purity wasestimated to be 95%).

Preparation of Compound 122

In a 40 ml vial equipped with a stir bar, compound 19 (70 mg, 0.20 mmol)and HATU (95 mg, 0.25 mmol) were dissolved in 3 ml of a mixture ofDMF:water (2:1). A solution of 4-cyanobenzylamine (33 mg, 0.25 mmol) anddiisopropylethylamine (0.17 ml, 1.00 mmol) was then added to compound 19solution at 0-5° C. The mixture was then stirred at room temperatureovernight. Upon the completion of the reaction, the mixture was dilutedwith EtOAc (50 ml), and then washed with water and brine (50 ml ofeach). The organic layer was then dried over anhydrous sodium sulfate,and the EtOAc was evaporated under vacuum. The residue was then purifiedby flash chromatography to give 53 mg of the product (yield: 60%);Compound 122 was characterized by LCMS (441 [M+H]⁺; and purity wasestimated to be 90%).

Preparation of Compound 123

In a 40 ml vial equipped with a stir bar, compound 19 (70 mg, 0.20 mmol)and HATU (95 mg, 0.25 mmol) were dissolved in 3 ml of a mixture ofDMF:water (2:1). A solution of 2-cyanobenzylamine (33 mg, 0.25 mmol) anddiisopropylethylamine (0.17 ml, 1.00 mmol) was then added to compound 19solution at 0-5° C. The mixture was then stirred at room temperatureovernight. Upon the completion of the reaction, the mixture was dilutedwith EtOAc (50 ml), and then washed with water and brine (50 ml ofeach). The organic layer was then dried over anhydrous sodium sulfate,and the EtOAc was evaporated under vacuum. The residue was then purifiedby flash chromatography to give 45 mg of the product (yield: 51%);Compound 123 was characterized by LCMS (441 [M+H]⁺; and purity wasestimated to be 90%).

Preparation of Compound 124

In a 40 ml vial equipped with a stir bar, compound 19 (70 mg, 0.20 mmol)and HATU (95 mg, 0.25 mmol) were dissolved in 3 ml of a mixture ofDMF:water (2:1). A solution of 3-cyanobenzylamine (33 mg, 0.25 mmol) anddiisopropylethylamine (0.17 ml, 1.00 mmol) was then added to compound 19solution at 0-5° C. The mixture was then stirred at room temperatureovernight. Upon the completion of the reaction, the mixture was dilutedwith EtOAc (50 ml), and then washed with water and brine (50 ml ofeach). The organic layer was then dried over anhydrous sodium sulfate,and the EtOAc was evaporated under vacuum. The residue was then purifiedby flash chromatography to give 49 mg of the product (yield: 56%);Compound 124 was characterized by LCMS (441 [M+H]⁺; and purity wasestimated to be 90%).

Preparation of Compound 125

In a 40 ml vial equipped with a stir bar, compound 19 (70 mg, 0.20 mmol)and HATU (95 mg, 0.25 mmol) were dissolved in 3 ml of a mixture ofDMF:water (2:1). A solution of 2-methoxybenzylamine (34 mg, 0.25 mmol)and diisopropylethylamine (0.17 ml, 1.00 mmol) was then added tocompound 19 solution at 0-5° C. The mixture was then stirred at roomtemperature overnight. Upon the completion of the reaction, the mixturewas diluted with EtOAc (50 ml), and then washed with water and brine (50ml of each). The organic layer was then dried over anhydrous sodiumsulfate, and the EtOAc was evaporated under vacuum. The residue was thenpurified by flash chromatography to give 51 mg of the product (yield:57%); Compound 125 was characterized by LCMS (446 [M+H]⁺; and purity wasestimated to be 95%).

Example 2: Cell Growth Inhibition

The drug concentration required to block net cell growth by 50% relativeto a control sample is measured as the GI₅₀. The GI₅₀s for several ofthe compounds of the application were assayed as described.

MTT assay: U87 and GL261 cells were seeded in 96-well plate (6×10³ cellsin 100 μl of DMEM+10% FBS media per well) and incubated overnight at 37°C. with 5% CO₂. All test compounds were diluted (10 point 2-fold serialdilution) in a separate 96-well plate to yield 10× of finalconcentrations (0.5-256 nM). A volume of 11 μl of 10× dilutions wasadded to appropriate wells (n=3). To value (reflecting the startingnumber of cells upon drug treatment) was determined by following stepsas described below. After 3 days incubation at 37° C. with 5% CO₂, 10 μlof MTT solution (5 mg/ml in PBS) was added to each well and plates wereincubated at 37° C. for 3 h to allow MTT to form formazan crystals byreacting with metabolically active cells. 100 μl of 20% SDS was added toeach well and plates were incubated overnight at 37° C. with 5% CO₂.Afterward, OD₅₇₀ was measured using microplate reader. The cell growthpercentage of control was calculated according to percentage ofcontrol=(T−T₀)/(C−T₀)×100% or OD value of the test well exposure to testdrug−OD value at time zero/(OD of the control well without drugtreatment−OD value at time zero)×100%. Growth inhibition curves and GI₅₀were determined using GraphPad Prism 5 software.

The GI₅₀ of representative compounds of the application against variouscell lines is shown in Table 2.

TABLE 2 GI₅₀ (nM) Cmpd No. GL261 U87 Jurkat HT-29 100 129, 127 203, 151101 76 96 102 24, 42 25, 37 103 113 146 104 3.0, 2.8, 3.8, 3.4, 3.9,6.8, 4.0, 3.5, 3.7, 4.8, 4.0, 7.2, 2.5, 2.3 2.5, 3.1 6.2, 5.3, 5.7,12.6, 10, 10, 6.9, 6.4, 6.1, 16.3, 15.6, 7.4, 5.3 13.1, 14.6, 15.2 1055.7, 6.9 10.8, 12.2 106 27.3, 30.9, 36.2, 59.1, 43.2 27.5, 19.5, 75.6,52.2, 40.4 107 19.4, 28.3 22.1, 23.4 108 6.8 6.6 3 109 >1024 >1024110 >1024 >1024 111 195, 170 239, 224 112 210, 240 352, 401 113 180,120, 99 212, 182, 103 46 114 340, 500  382, >1024 115 80, 29, 20, 17.330, 30, 15, 15.6 116 110, 90, 74 120, 115, 98 117 488, 387 >729 118 262621 119 164, 216, 139 129, 233, 224 120 17, 13.6, 18.9, 15.8, 13.4,20.2, 22.3, 18.4, 17.7, 18.6, 10.7 18.6 121 4.6, 6.5, 7.9, 3.2, 1.6, 5.07.9, 7.1, 5.2, 5.2, 3.3, 8.0 122 13.8, 18.9 24.7, 17.3 123 456 473 1241027 860 125 140, 158 195, 230 126 47.9, 38.6 41.9, 46.0 127 207 269 128303 377 129 51.7, 30.3   36, 38.1 130 111, 107 104, 135

Example 3: Pharmacokinetic of the Compounds of the Application

The pharmacokinetic properties of representative compounds of theapplication are listed in Table 3. The compounds of applicationdisplayed improved potency with similar pharmacokinetics, allowing fordecreased dosing.

TABLE 3 IV Administration (5 mg/kg) PO Administration C₀ t_(0.5) CLV_(ss) (20 mg/kg) Cmpd No. (ng/ml) (h) (L/h/kg) (L/kg) ¹AUC_(IV)¹AUC_(PO) C_(max) ²F (%) Cmpd Y 4620 0.364 1.81 0.962 553 217 2593 39.3120 1590 0.663 5.32 3.63 188 76.8 798 40.9 121 2848 0.959 1.74 2.24 575199 2170 34.8 ¹Dose-normalized AUC values (hr · kg · ng/mL/mg); ²F (%) =100 × AUC_(PO)/AUC_(IV)

Example 4: Brain Permeability of the Compounds of the Application

The brain permeability of representative compounds of the application islisted in Table 4. The compounds of application showed improvedbioavailability to the brain.

TABLE 4 Brain:Plasma (B:P) Average (ng/ml) time point (h) Compound YCompound 120 Compound 121 0.25 1.56 1.24 1.08 0.5 1.46 1.39 1.37 1 1.331.72 1.53 2 0.712 1.38 1.93 4 0.834 1.04 2.29 6 0.633 0.820 1.66 8 0.6851.12 1.24

Example 5: Effect on Compound 121 on 50 Cancer Cell Lines

The cell viability of 50 cancer cell lines was studied after treatmentwith Compound 121. Inhibition concentration values at 50% (IC₅₀) weredetermined using CellTiter-Glo luminescent cell viability assay afterincubation with different compound concentrations. GI₅₀ values weredetermined according to the examples described above. Each cell line wastreated with Compound 121, a standard chemotherapy drug as a referencecontrol, and culture medium as a vehicle control.

All cells were cultured in media supplemented with 10-15% FBS at 37° C.in the presence of 5% CO₂ and at 95% humidity. The culture medium waspurchased from GIBCO or Sigma, USA. Cisplatin was chosen as thereference control and purchased from Hospira Australia Pty Ltd. The celllines studied are presented in Table 5.

TABLE 5 No. Cell Line Name Tissue Origin 1 HT-1376 Bladder 2 HL-60 Blood3 HuT 78 4 K-562 5 KARPAS-299 6 Molt-4 7 Raji 8 RPMI 8226 9 143B Bone 10A-172 Brain and Nerves 11 SK-N-FI 12 TJ905 13 U251 14 BT474 Breast 15MDA-MB-231 16 MDA-MB-453 17 MDA-MB-468 18 MX-1 19 HeLa Cervix 20 HCT-116Colorectum 21 HCT-15 22 HT-29 23 KYSE-150 Esophagus 24 786-O Kidney 25HuCCT1 Liver 26 HUH-7 27 JHH-5 28 EBC-1 Lung 29 NCI-H1155 30 NCI-H197531 NCI-H209 32 NCI-H226 33 A-673 Muscle 34 OVCAR-3 Ovary 35 SK-OV-3 36AsPC-1 Pancreas 37 KP4 38 FaDu Pharynx 39 JEG-3 Placenta 40 22Rv1Prostate 41 PC-3 42 A2058 Skin 43 SK-MEL-28 44 HT-1080 Soft tissue 45NCI-N87 Stomach/Gastric 46 SNU-5 47 SW579 Thyroid 48 SCC-4 Tongue 49 AN3CA Uterus 50 MES-SA/DX5

Cells were harvested during a logarithmic growth period and cell numbercount was determined using Count-star. Cell concentrations were adjustedto 4.44×10⁴ cells/mL with respective culture medium. 90 μL of cellsuspensions were added to two 96-well plates (plates A and B) with afinal cell density of 4×10³ cells/well.

10 μL of culture medium was added to each well of plate A for T0reading. The plate was allowed to equilibrate at room temperature forapproximately 30 min. 50 μL of CellTiter-Glo was added to each well andthe contents were mixed for 5 min on an orbital shaker to induce celllysis. The plate was allowed to incubate at room temperature for 20 minto stabilize luminescent signal.

10 μM Compound 121 in media was serially diluted 3.16-fold to achieve 9dose levels. Similarly, 100 μM reference control in media was seriallydiluted 3.16-fold to prepare reference control solutions. 10 μL drugsolution and 10 μL of reference control was dispensed into each well inplate B.

Test plate B was incubated for 72 h in a humidified incubator at 37° C.in the presence of 5% CO₂ and then subjected to CTG assay. The plate wasallowed to equilibrate at room temperature for about 30 min. 50 μL ofCellTiter-Glo was added to each well and the contents were mixed for 5min on an orbital shaker to induce cell lysis. The plate was allowed toincubate at room temperature for 20 min to stabilize luminescent signal.

IC₅₀ and GI₅₀ values for each of the 50 cell lines are presented inTable 6 and were calculated based on the dose-response curves depictedin FIGS. 1-50. The dose-reponse curves were fitted using nonlinearregression model with a sigmoidal dose response. The formula forcalculating survival rate was calculated by the formula:Survivalrate(%)=(Lum_(Test article)−Lum_(Medium control))/(Lum_(None treated)−Lum_(Medium control))×100.

TABLE 6 Absolute IC50 (μM) Absolute GI50 (μM) % inhibition at top conc.Cell Compound Compound Compound No. Cell lines 121 Cisplatin 121Cisplatin 121 Cisplatin 1 TJ905 0.004 9.85 0.004 6.56 69.96% 80.57% 2JEG-3 0.009 9.40 0.008 5.50 86.49% 99.90% 3 SW579 0.007 2.24 0.006 1.8388.21% 99.88% 4 KYSE-150 0.006 8.14 0.005 6.26 80.04% 91.28% 5 I43B0.008 1.08 0.008 1.02 97.85% 99.94% 6 HT-1080 0.005 2.22 0.005 1.9897.15% 99.59% 7 KP4 0.008 8.80 0.007 6.87 90.78% 98.30% 8 HCT-15 0.0064.76 0.005 4.27 96.76% 98.22% 9 SK-N-FI 0.004 9.26 0.003 5.80 91.37%99.77% 10 HuCCT1 0.004 8.44 0.004 6.59 53.99% 90.42% 11 AsPC-1 >10 3.310.012 2.73 51.16% 72.39% 12 OVCAR-3 0.006 4.29 0.005 3.81 64.84% 91.14%13 MDA-MB- 0.004 9.51 0.004 7.05 67.55% 96.82% 453 14 RPMI 8226 0.0063.62 0.005 2.38 94.85% 99.76% 15 NCI-H226 0.013 7.36 0.010 5.72 61.68%94.81% 16 HCT-116 0.009 4.35 0.009 4.14 94.36% 95.29% 17 JHH-5 0.0072.27 0.007 1.97 80.50% 87.18% 18 A-172 0.007 20.33 0.006 15.86 92.77%93.09% 19 SK-OV-3 0.004 6.69 0.004 5.08 66.23% 81.79% 20 MDA-MB- 0.0090.93 0.007 0.65 80.02% 99.91% 468 21 NCI-H1155 0.007 1.75 0.006 1.5287.27% 90.61% 22 MX-1 0.018 7.12 0.011 5.69 66.85% 98.97% 23 HT-13760.009 3.26 0.006 2.64 52.98% 91.76% 24 HUH-7 0.009 3.54 0.007 2.6160.77% 93.92% 25 HeLa 0.004 0.33 0.004 0.30 89.52% 99.60% 26 K-562 0.0064.51 0.006 4.21 98.12% 97.94% 27 HT-29 0.004 9.80 0.004 8.78 78.51%89.05% 28 NCI-H1975 0.006 6.93 0.006 5.52 83.68% 98.75% 29 FaDu 0.0082.25 0.007 1.96 85.88% 98.16% 30 HL-60 0.008 1.46 0.007 1.34 99.81%99.99% 31 MDA-MB- >10 23.66 0.020 18.55 45.84% 85.68% 231 32 786-O 0.0051.77 0.005 1.60 85.35% 98.46% 33 Raji 0.005 1.97 0.005 1.74 94.22%94.98% 34 Molt-4 0.014 0.71 0.013 0.61 99.59% 99.96% 35 KARPAS- 0.0061.63 0.006 1.49 99.37% 99.99% 299 36 BT474 >10 45.14 0.012 39.33 37.93%59.96% 37 NCI-H209 0.020 0.23 0.017 0.14 73.69% 98.81% 38 PC-3 0.0085.94 0.008 4.68 93.31% 83.88% 39 MES- 0.007 2.21 0.007 1.96 97.85%99.94% SA/DX5 40 SK-MEL-28 >10 8.90 0.004 7.09 52.92% 99.29% 41 AN3 CA0.005 4.38 0.005 3.68 98.57% 99.95% 42 HuT 78 0.009 0.66 0.008 0.5095.15% 98.27% 43 22Rv1 0.006 3.07 0.005 1.88 89.05% 98.28% 44 A20580.008 3.11 0.008 2.38 98.14% 99.85% 45 SCC-4 0.006 4.15 0.005 3.4386.11% 99.29% 46 SNU-5 0.012 2.50 0.011 2.15 96.19% 97.80% 47 EBC-10.004 17.34 0.004 11.82 56.75% 84.49% 48 A-673 0.004 1.12 0.003 0.4086.11% 99.59% 49 U251 0.009 3.98 0.009 3.07 75.02% 87.70% 50 NCI-N870.004 2.26 0.004 0.88 49.56% 90.08%

Example 6: Compound 121 Delays Growth of Human U87 Glioblastoma Cells inXenograft Model

The anti-tumor activity of Compound 121, as a single agent, was studiedin a U87-luc human glioblastoma subcutaneous xenograft tumor model.Significant endpoints were used to assess the treatment effects onsubcutaneous tumor growth, as determined by tumor growth inhibition.

Human glioblastoma U87 cells (1×10⁶ cells) were implanted into the rightflank of athymic nude mice via subcutaneous injection. Dosing wasinitiated when the average tumor size reached 90-100 mm³, which wasdesignated as Day 1.

Compound 121 was dosed at 5 mg/kg once per day through Days 1-7 anddosed 2.5 mg/kg once per day through Days 15-21. A control group of mice(N=7) was administered a vehicle per the same schedule. Tumor volume wasdetermined every 2 to 3 days via bidimensional caliper measurements.Body weight and general observations were recorded.

The mice were euthanized once the tumor reached 2000 mm³ in volume.

Tumor growth inhibition (TGI) was calculated with the following formula:TGI=(1−(mean volume of treated tumors)/(mean volume of controltumors))×100.

Compound 121 repressed tumor growth based according to evaluation oftumor volumes in individual mice over time (FIG. 53A and FIG. 53B).Therefore, the time to terminal sacrifice (based on tumor volume) wassignificantly extended compared to the control group (P<0.05; FIG. 53C).On Day 12, the mean tumor volume in the Compound 121-treated group wassignificantly reduced compared to the control group (P<0.05). Mean tumorvolume and % TGI at Day 12 is provided in Table 7.

TABLE 7 Mean Tumor Volume and Tumor Growth Inhibition in a U87-luc HumanGlioblastoma Subcutaneous Xenograft Tumor Model Orally Dosed withCompound 121 Compared to a Control. Mean Tumor Group Volume (mm3) ± SEM% TGI Control 1615.1 ± 201.3 — Compound 121 442.9 ± 67.2 76.8

Example 7: Compound 121 Extends Survival and Supports Long-Term TumorControl in the GL261 Murine Model of Glioblastoma

The anti-tumor activity of Compound 121, as a single agent, was studiedin the GL261 murine model of human glioblastoma. Murine GL261glioblastoma cells were injected intra-cranially into syngeneic,immune-competent hosts (C57BL/6). In order for oral therapeutics to beeffective, it is required that the therapeutic be able to cross theblood-brain barrier in order to achieve sufficient levels in the brainto exert an anti-tumor effect. Survival was the major endpoint for thestudy. The mice either succumbed to the tumor or were euthanized basedon severity of tumor-dependent morbidity. Mice that achieved long-termsurvival (>80 days) were re-challenged with a sub-cutaneous injection ofGL261 cells to assess the development of a durable immune response toGL261. Mice that underwent the re-challenge phase were not treated withCompound 121.

GL261 cells (1×10⁵ cells) were implanted into the brain of a C57BL/6host using stereotactice injection. Compound 121 was dosed orally onceper day at 1 mg/kg (N=10) for 45 days beginning 3 days post-tumor cellimplantation. Compound Y was dosed orally once per day at 5 mg/kg (N=10)for 45 days beginning 3 days post-tumor implantation. A vehicle wasadministered to a control group of mice (N=10) per the same schedule.

Mice were monitored for signs of tumor dependent morbidity, includinghead tilt, hunching, ataxia, and limb weakness. Mice were euthanizedwhen cumulative signs of high tumor burden were evident.

Re-challenge phase: Mice surviving past 80 days were injected with GL261cell subcutaneously on Day 93. A control group (naïve C57BL/6 mice, N=5)were also injected with GL261 cells subcutaneously. Tumor volumes werecalculated from bidimensional caliper measurements every 3 to 4 days.Further, all mice were administered oral doses of a Bifidobacteriummixture on three separate occasions. The objective of the administrationof Bifidobacterium was to transiently modify the intestinal microbiomeas a means to influence the immune response to GL261. Based on theobserved survival rates in the control group, the bacterial gavages hadminimal, if any, impact on intra-cranial growth of GL261.

Compound 121 significantly extended survival when compared to vehiclecontrol (P<0.5). Survival was supported beyond 80 days in 2 of the 10mice treated, as shown in FIG. 54A. The two mice with a long termsurvival (LTS) past 60 days were re-challenged with a sub-cutaneousinjection of GL261 cells in the flank. Three naïve C57BL/6 mice werealso injected subcutaneously with GL261 cells as a control. Tumorsfailed to grow in both LTS mice, whereas tumor growth was readilyevident in each of the three control mice, as shown in FIG. 54B. Theseobservations were consistent with the generation of a durable immuneresponse to GL261 in animals that achieved LTS with Compound 121 oraltherapy.

Compound Y, a closely related analog to Compound 121, had only amarginal, insignificant effect on survival when dosed at 5 mg/kg;however, Compound Y demonstrated activity when dosed once daily at ≥20mg/kg.

Other Embodiments

While the application has been described in conjunction with thedetailed description thereof, the foregoing description is intended toillustrate and not limit the scope of the application, which is definedby the scope of the appended claims. Other aspects, advantages, andmodifications are within the scope of the following claims. It will beunderstood by those skilled in the art that various changes in form anddetails may be made therein without departing from the scope of theapplication encompassed by the appended claims.

The invention claimed is:
 1. A compound of formula (VIIa), (VIIb),(VIIc), (VIId), or (VIIe):

or a pharmaceutically acceptable salt or solvate thereof, wherein: n2 is0, 1, 2, or 3; n3 is 0, 1, or 2; A¹, A², and A³ are each independentlyCR⁶¹ or N, and wherein only one of A¹, A², and A³ is N; each R⁶¹ isindependently H or R⁶; R¹ and R² are each independently H, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, or O—(C₁-C₆ alkyl); alternatively, R¹ andR², together with the carbon atom to which they are attached, form a 3-8membered saturated, unsaturated, or partially saturated carbocycle, or asaturated, unsaturated, or partially saturated heterocycle comprisingone or two 5-7 membered rings and one or more heteroatoms selected fromN, O, and S; alternatively, one of R¹ and R², together with the carbonatom to which R¹ or R² is attached and the adjacent

ring, form a 7-12 membered saturated, unsaturated, or partiallysaturated carbocycle, or a 7-12 membered saturated, unsaturated, orpartially saturated heterocycle comprising one or more heteroatomsselected from N, O and S; R³ is C₁-C₆ alkyl; R⁵ is (a) halogen, (b) OH,(c) CONH₂, (d) COOH, (e) CN, (f) N₃, (g) C₁-C₆ alkyl, (h) C₂-C₆ alkenyl,(i) C₂-C₆ alkynyl, (j) O—(C₁-C₆ alkyl), (k) O—(C₂-C₆ alkenyl), (l)O—(C₂-C₆ alkynyl), (m) COO—(C₁-C₆ alkyl), (n) COO—(C₂-C₆ alkenyl), (o)COO—(C₂-C₆ alkynyl), (p) CONH—(C₁-C₆ alkyl), (q) CONH—(C₂-C₆ alkenyl),(r) CONH—(C₂-C₆ alkynyl), (s) CON(C₁-C₆ alkyl)₂, (t) CON(C₂-C₆alkenyl)₂, (u) CON(C₂-C₆ alkenyl)₂, (v1) (C₁-C₆ alkyl)_(v)-NH(C₁-C₆alkyl), (v2) (C₁-C₆ alkyl)_(v)-NH(C₂-C₆ alkenyl), (v3) (C₁-C₆alkyl)_(v)-NH(C₂-C₆ alkynyl), (w1) (C₂-C₆ alkenyl)_(v)-NH(C₁-C₆ alkyl),(w2) (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆ alkenyl), (w3) (C₂-C₆alkenyl)_(v)-NH(C₂-C₆ alkynyl), (x1) (C₂-C₆ alkynyl)_(v)-NH(C₁-C₆alkyl), (x2) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆ alkenyl), (x3) (C₂-C₆alkynyl)_(v)-NH(C₂-C₆ alkynyl), (y1) (C₁-C₆ alkyl)_(w)-N(C₁-C₆ alkyl)₂,(y2) (C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkenyl)₂, (y3) (C₁-C₆ alkyl)_(w)-N(C₂-C₆alkynyl)₂, (z1) (C₂-C₆ alkenyl)_(w)-N(C₁-C₆ alkyl)₂, (z2) (C₂-C₆alkenyl)_(w)-N(C₂-C₆ alkenyl)₂, (z3) (C₂-C₆ alkenyl)_(w)-N(C₂-C₆alkynyl)₂, (aa1) (C₂-C₆ alkynyl)_(w)-N(C₁-C₆ alkyl)₂, (aa2) (C₂-C₆alkynyl)_(w)-N(C₂-C₆ alkenyl)₂, (aa3) (C₂-C₆ alkynyl)_(w)-N(C₂-C₆alkenyl)₂, (bb) S—(C₁-C₆ alkyl), (cc) S(O)—(C₁-C₆ alkyl), (dd)S(O)₂—(C₁-C₆ alkyl), (ee) S—(C₂-C₆ alkenyl), (ff) S(O)—(C₂-C₆ alkenyl),(gg) S(O)₂—(C₂-C₆ alkenyl), (hh) S—(C₂-C₆ alkynyl), (ii) S(O)—(C₂-C₆alkynyl), (jj) S(O)₂—(C₂-C₆ alkynyl), (kk) an aromatic, saturated,unsaturated, or partially saturated carbocycle comprising one or two 3-8membered rings, or (ll) an aromatic, saturated, unsaturated, orpartially saturated heterocycle comprising one or two 5-7 membered ringsand one or more heteroatoms selected from N, O and S, wherein each of(g)-(ll) is optionally substituted with one or more R⁸; each R⁶ isindependently (a) halogen, (b) OH, (c) CONH₂, (d) COOH, (e) CN, (f) N₃,(g) C₁-C₆ alkyl, (h) C₂-C₆ alkenyl, (i) C₂-C₆ alkynyl, (j) O—(C₁-C₆alkyl), (k) O—(C₂-C₆ alkenyl), (l) O—(C₂-C₆ alkynyl), (m) COO—(C₁-C₆alkyl), (n) COO—(C₂-C₆ alkenyl), (o) COO—(C₂-C₆ alkynyl), (p)CONH—(C₁-C₆ alkyl), (q) CONH—(C₂-C₆ alkenyl), (r) CONH—(C₂-C₆ alkynyl),(s) CON(C₁-C₆ alkyl)₂, (t) CON(C₂-C₆ alkenyl)₂, (u) CON(C₂-C₆ alkynyl)₂,(v1) (C₁-C₆ alkyl)-NH(C₁-C₆ alkyl), (v2) (C₁-C₆ alkyl)_(v)-NH(C₂-C₆alkenyl), (v3) (C₁-C₆ alkyl)_(v)-NH(C₂-C₆ alkynyl), (w1) (C₂-C₆alkenyl)_(v)-NH(C₁-C₆ alkyl), (w2) (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆alkenyl), (w3) (C₂-C₆ alkenyl)_(v)-NH(C₂-C₆ alkynyl), (x1) (C₂-C₆alkynyl)_(v)-NH(C₁-C₆ alkyl), (x2) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆alkenyl), (x3) (C₂-C₆ alkynyl)_(v)-NH(C₂-C₆ alkynyl), (y1) (C₁-C₆alkyl)_(w)-N(C₁-C₆ alkyl)₂, (y2) (C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkenyl)₂,(y3) (C₁-C₆ alkyl)_(w)-N(C₂-C₆ alkynyl)₂, (z1) (C₂-C₆alkenyl)_(w)-N(C₁-C₆ alkyl)₂, (z2) (C₂-C₆ alkenyl)_(w)-N(C₂-C₆alkenyl)₂, (z3) (C₂-C₆ alkenyl)_(w)-N(C₂-C₆ alkynyl)₂, (aa1) (C₂-C₆alkynyl)_(w)-N(C₁-C₆ alkyl)₂, (aa2) (C₂-C₆ alkynyl)_(w)-N(C₂-C₆alkenyl)₂, (aa3) (C₂-C₆ alkynyl)_(w)-N(C₂-C₆ alkynyl)₂, (bb) S—(C₁-C₆alkyl), (cc) S(O)—(C₁-C₆ alkyl), (dd) S(O)₂—(C₁-C₆ alkyl), (ee) S—(C₂-C₆alkenyl), (ff) S(O)—(C₂-C₆ alkenyl), (gg) S(O)₂—(C₂-C₆ alkenyl), (hh)S—(C₂-C₆ alkynyl), (ii) S(O)—(C₂-C₆ alkynyl), (jj) S(O)₂—(C₂-C₆alkynyl), (kk) an aromatic, saturated, unsaturated, or partiallysaturated carbocycle comprising one or two 3-8 membered rings, or (ll)an aromatic, saturated, unsaturated, or partially saturated heterocyclecomprising one or two 5-7 membered rings and one or more heteroatomsselected from N, O and S, wherein each of (g)-(ll) is optionallysubstituted with one or more R⁹; each R⁸ is independently halogen, OH,O—(C₁-C₆ alkyl), C₁-C₆ haloalkyl, COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl),CON(C₁-C₆ alkyl)₂, COOH, CN, N₃, 5-6 membered saturated, unsaturated, orpartially saturated carbocycle, or 5-6 membered saturated, unsaturated,or partially saturated heterocycle comprising one or more heteroatomsselected from N, O and S, each R⁹ is independently halogen, OH, O—(C₁-C₆alkyl), COO—(C₁-C₆ alkyl), CONH—(C₁-C₆ alkyl), CON(C₁-C₆ alkyl)₂, COOH,CN, N, 5-6 membered saturated, unsaturated, or partially saturatedcarbocycle, or 5-6 membered saturated, unsaturated, or partiallysaturated heterocycle comprising one or more heteroatoms selected fromN, O and S, v is 0 or 1, and w is 0 or
 1. 2. The compound of claim 1,wherein R⁵ is halogen, C₁-C₆ alkyl, or O—C₁-C₆ alkyl.
 3. The compound ofclaim 1, wherein R⁵ is C₁-C₆ alkyl.
 4. The compound of claim 1, whereinR⁵ is methyl.
 5. The compound of claim 1, wherein R⁶ is halogen, C₁-C₆alkyl, O—C₁-C₆ alkyl, or CN.
 6. The compound of claim 1, wherein R⁶ ishalogen.
 7. The compound of claim 1, wherein R⁶ is fluoro.
 8. Thecompound of claim 1, wherein R⁶ is at the 2- or 4-position.
 9. Thecompound of claim 1, wherein R³ is methyl.
 10. The compound of claim 1,wherein the compound is

or a pharmaceutically acceptable salt or solvate thereof.
 11. Apharmaceutical composition comprising the compound of claim 1, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.
 12. The compound of claim 1,wherein the compound is

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, wherein the compound is


14. The compound of claim 1, wherein the compound is of formula (VIIb):


15. The compound of claim 1, wherein the compound is of formula (VIIa):


16. The compound of claim 1, wherein the compound is of formula (VIIc):


17. The compound of claim 1, wherein the compound is of formula (VIId):


18. The compound of claim 1, wherein R¹ and R² are each H.
 19. Thecompound of claim 1, wherein n2 is 0 or
 1. 20. The compound of claim 1,wherein n3 is 0 or
 1. 21. The compound of claim 1, selected from thegroup consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 22. Thecompound of claim 1, selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 23. Apharmaceutical composition comprising the compound of claim 13, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.
 24. A compound of the followingstructure:

or a pharmaceutically acceptable salt or solvate thereof.
 25. Apharmaceutical composition comprising the compound of claim 24, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.